Substituted imidazolones, compositions containing such compounds and methods of use

ABSTRACT

The present invention relates to compounds of the general structure shown in Formula (A): (A): and includes pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds. Pharmaceutical compositions and methods of treatment are also included.

FIELD OF THE INVENTION

The present invention relates to compounds that are useful as glucagonreceptor antagonists, compositions comprising these compounds, andmethods for their use in treating, preventing, or delaying the onset oftype 2 diabetes and related conditions.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease state or process derived from multiplecausative factors and is characterized by elevated levels of plasmaglucose (hyperglycemia) in the fasting state or after administration ofglucose during a glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with a wide range of pathologies. Frankdiabetes mellitus (e.g., fasting blood glucose levels above about 126mg/dL) is associated with increased and premature cardiovascular diseaseand premature mortality, and is related directly and indirectly tovarious metabolic conditions, including alterations of lipid,lipoprotein, apolipoprotein metabolism and other metabolic andhemodynamic diseases. As such, the diabetic patient is at increased riskof macrovascular and microvascular complications. Such complications canlead to diseases and conditions such as coronary heart disease, stroke,peripheral vascular disease, hypertension, nephropathy, neuropathy, andretinopathy. Accordingly, therapeutic control and correction of glucosehomeostasis is regarded as important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), the diabeticpatient's pancreas is incapable of producing adequate amounts ofinsulin, the hormone which regulates glucose uptake and utilization bycells. In type 2 diabetes, or noninsulin dependent diabetes mellitus(NIDDM), patients often produce plasma insulin levels comparable tothose of nondiabetic subjects; however, the cells of patients sufferingfrom type 2 diabetes develop a resistance to the effect of insulin, evenin normal or elevated plasma levels, on glucose and lipid metabolism,especially in the main insulin-sensitive tissues (muscle, liver andadipose tissue).

Insulin resistance is not associated with a diminished number ofcellular insulin receptors but rather with a post-insulin receptorbinding defect that is not well understood. This cellular resistance toinsulin results in insufficient insulin activation of cellular glucoseuptake, oxidation, and storage in muscle, and inadequate insulinrepression of lipolysis in adipose tissue, and of glucose production andsecretion in the liver. A net effect of decreased sensitivity to insulinis high levels of insulin circulating in the blood without appropriatereduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a riskfactor for developing hypertension and may also contribute to vasculardisease.

The available treatments for type 2 diabetes, some of which have notchanged substantially in many years, are used alone and in combination.Many of these treatments have recognized limitations, however. Forexample, while physical exercise and reductions in dietary intake offat, high glycemic carbohydrates, and calories can dramatically improvethe diabetic condition, compliance with this treatment is very poorbecause of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic beta-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate insulin-resistance in tissues. However, dangerously low levelsof plasma glucose can result from administration of insulin or insulinsecretagogues (sulfonylureas or meglitinide), and an increased level ofinsulin resistance due to the even higher plasma insulin levels canoccur. The biguanides are a separate class of agents that can increaseinsulin sensitivity and bring about some degree of correction ofhyperglycemia. These agents, however, can induce lactic acidosis, nauseaand diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are another classof compounds that have proven useful for the treatment of type 2diabetes. These agents increase insulin sensitivity in muscle, liver andadipose tissue in several animal models of type 2 diabetes, resulting inpartial or complete correction of the elevated plasma levels of glucosewithout occurrence of hypoglycemia. The glitazones that are currentlymarketed are agonists of the peroxisome proliferator activated receptor(PPAR), primarily the PPAR-gamma subtype. PPAR-gamma agonism isgenerally believed to be responsible for the improved insulinsensitization that is observed with the glitazones. Newer PPAR agoniststhat are being tested for treatment of Type II diabetes are agonists ofthe alpha, gamma or delta subtype, or a combination thereof, and in manycases are chemically different from the glitazones (i.e., they are notthiazolidinediones). Serious side effects (e.g. liver toxicity) havebeen noted in some patients treated with glitazone drugs, such astroglitazone.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV)enzyme are also under investigation or available as drugs for thetreatment of diabetes, and particularly type 2 diabetes. Examplesinclude alogliptin (Takeda), saxagliptin (Brystol-Myers Squibb),sitagliptin (Januvia™, Merck), vildagliptin (Galvus™, Novartis),denagliptin (GlaxoSmithKline), ABT-279 and ABT-341 (Abbott), ALS-2-0426(Alantos), ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim),SYR-322 (Takeda), compounds disclosed in U.S. Pat. No. 6,699,871, MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) and combinationsthereof.

Additional methods of treating hyperglycemia and diabetes are currentlyunder investigation. New biochemical approaches include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Other approaches to treating hyperglycemia, diabetes, and indicationsattendant thereto have focused on the glucagon hormone receptor.Glucagon and insulin are the two primary hormones regulating plasmaglucose levels. Insulin, released in response to a meal, increases theuptake of glucose into insulin-sensitive tissues such as skeletal muscleand fat. Glucagon, which is secreted by alpha cells in pancreatic isletsin response to decreased postprandial glucose levels or during fasting,signals the production and release of glucose from the liver. Glucagonbinds to specific receptors in liver cells that trigger glycogenolysisand an increase in gluconeogenesis through cAMP-mediated events. Theseresponses generate increases in plasma glucose levels (e.g., hepaticglucose production), which help to regulate glucose homeostasis.

Type 2 diabetic patients typically have fasting hyperglycemia that isassociated with elevated rates of hepatic glucose production. This isdue to increased gluconeogenesis coupled with hepatic insulinresistance. Such patients typically have a relative deficiency in theirfasting and postprandial insulin-to-glucagon ratio that contributes totheir hyperglycemic state. Several studies have demonstrated thathepatic glucose production correlates with fasting plasma glucoselevels, suggesting that chronic hepatic glucagon receptor antagonismshould improve this condition. In addition, defects in rapidpostprandial insulin secretion, as well as ineffective suppression ofglucagon secretion, lead to increased glucagon levels that elevatehepatic glucose production and contribute to hyperglycemia. Suppressionof elevated postprandial glucagon levels in type 2 diabetics withsomatostatin has been shown to lower blood glucose concentrations. Thisindicates that acute postprandial glucagon receptor antagonism wouldalso be beneficial. Based on these and other data, glucagon receptorantagonism holds promise as a potential treatment of type 2 diabetes byreducing hyperglycemia. There is thus a need in the art forsmall-molecule glucagon receptor antagonists with good safety profilesand efficacy that are useful for the treatment of hyperglycemia,diabetes, and related metabolic diseases and indications. The presentinvention addresses that need.

SUMMARY OF THE INVENTION

The present invention relates to compounds represented by Formula (A):

as well as the pharmaceutically acceptable salts, solvates, esters,prodrugs, tautomers and isomers of said compounds. Pharmaceuticalcompositions and methods of treatment are also included.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention relates to compounds of thegeneral structure shown in Formula (A):

and includes pharmaceutically acceptable salts thereof, wherein:

A compound represented by Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is selected from the group consisting of a bond, —N(R⁴)—,—N(R⁴)—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—N(R⁴)—, —O—,—O—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—O— and—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—,

each q is independently an integer from 0 to 5;

each r is independently an integer from 0 to 3;

s is an integer from 0 to 5;

ring B is a phenyl ring, wherein said phenyl ring is (in addition to the-L¹- and —C(O)N(R³)—Z moieties shown) optionally further substitutedwith one or more substituents R^(a), wherein each R^(a) (when present)is independently selected from the group consisting of halo, —OH, —SF₅,—OSF₅, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy and—O-haloalkyl,

or ring B is a 5-membered heteroaromatic ring containing from 1 to 3ring heteroatoms independently selected from N, O, and S, wherein said5-membered heteroaromatic ring is (in addition to the -L¹- and—C(O)N(R³)—Z moieties shown) optionally further substituted with one ormore substituents R^(a), wherein each R^(a) (when present) isindependently selected from the group consisting of halo, —OH, —SF₅,—OSF₅, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy and—O-haloalkyl,

or ring B is a 6-membered heteroaromatic ring containing from 1 to 3ring nitrogen atoms, wherein said 6-membered heteroaromatic ring is (inaddition to -L¹- and —C(O)N(R³)Z moieties shown) optionally furthersubstituted with one or more substituents R^(a), wherein each R^(a)(when present) is independently selected from the group consisting ofhalo, —OH, —SF₅, —OSF₅, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and—O-haloalkyl;

each V is independently selected from the group consisting of alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of V may only be connectedthrough carbon, and wherein said alkyl, said heteroalkyl, said alkenyl,said alkynyl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl,said heterocycloalkenyl, said aryl, and said heteroaryl of V areunsubstituted or optionally substituted with one or more groupsindependently selected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO,

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl,

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl,

(4) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl,

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl, and—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)— heterocycloalkenyl,

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl,

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl,

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl,

(10) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl,

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R²¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl of (7), said heterocycloalkyl of (3), saidheterocycloalkenyl of (5), and said heteroaryl of (11) may be connectedthrough any available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of (1) through(11) are unsubstituted or substituted with one or more groupsindependently selected from R²,

G is selected from the group consisting of:

(1a) hydrogen, halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and—CHO,

(2a) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl,

(3a) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl,

(4a) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl,

(5a) heterocycloalkenyl, —O-heterocycloalkenyl,—C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl, —N(R¹)-heterocycloalkenyl,—C(O)—N(R²¹)-heterocycloalkenyl, and —N(R²¹)—C(O)-heterocycloalkenyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl, —N(R²¹)—S(O)-heterocycloalkenyl,—N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl,

(6a) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7a) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl,

(8a) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl,

(9a) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl,

(10a) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl,

(11a) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl;

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of G may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of G areunsubstituted or substituted with one or more groups independentlyselected from R²,

each R¹ is independently selected from:

(1b) hydrogen and —CHO,

(2b) cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl, —S(O)-cycloalkyl and—S(O)₂-cycloalkyl,

(3b) heterocycloalkyl, —C(O)-heterocycloalkyl, —CO₂-heterocycloalkyl,—S(O)-heterocycloalkyl and —S(O)₂-heterocycloalkyl,

(4b) cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S(O)-cycloalkenyl and —S(O)₂-cycloalkenyl,

(5b) heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S(O)-heterocycloalkenyl and—S(O)₂-heterocycloalkenyl,

(6b) alkyl, —C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl and —S(O)₂-alkyl,

(7b) heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl, —S(O)-heteroalkyland —S(O)₂-heteroalkyl,

(8b) alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S(O)-alkenyl and—S(O)₂-alkenyl,

(9b) alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S(O)-alkynyl and—S(O)₂-alkynyl, (10b) aryl, —C(O)-aryl, —CO₂-aryl, —S(O)-aryl and—S(O)₂-aryl,

(11b) heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S(O)-heteroaryland —S(O)₂-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R¹ may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R¹ areunsubstituted or substituted with one or more groups independentlyselected from R²;

each R²¹ is independently selected from H and C₁₋₆alkyl;

each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO,

(2c) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl,

(3c) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl,

(4c) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl,

(5c) heterocycloalkenyl, —O-heterocycloalkenyl,—C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl, —N(R⁶)-heterocycloalkenyl,—C(O)—N(R²¹)-heterocycloalkenyl, and —N(R²¹)—C(O)-heterocycloalkenyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl, —N(R²¹)—S(O)-heterocycloalkenyl,—N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7c) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl,

(8c) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl,

(9c) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl,

(10c) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R² may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R² areunsubstituted or substituted with one or more groups independentlyselected from R⁷,

R³ is selected from H and lower alkyl;

Z is a moiety selected from —(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH,—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH, —(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)Oalkyl,—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)Oalkyl,

—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)-Q, and —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)-Q,

wherein Q is a moiety selected from the group consisting of:

wherein each R¹⁰ is independently H or alkyl;

m is an integer from 0 to 5;

n is an integer from 0 to 5;

p is an integer from 0 to 5;

each R⁴ is independently selected from H, —OH, lower alkyl, haloalkyl,alkoxy, heteroalkyl, cyano-substituted lower alkyl, hydroxy-substitutedlower alkyl, cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, andheterocycloalkyl, —O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl;

each R^(5A) is independently selected from H, alkyl, haloalkyl,heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl,cycloalkyl, -alkyl-cycloalkyl, and heterocycloalkyl,-alkyl-heterocycloalkyl,

or, alternatively, two R^(5A) groups are taken together with the carbonatom to which they are attached to form a carbonyl group, aspirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, ora substituted oxime group, said oxime substituents being independentlyselected from alkyl, haloalkyl, hydroxyl-substituted alkyl, andcycloalkyl;

each R⁵ is independently selected from H, —OH, alkyl, haloalkyl, alkoxy,heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl,cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, andheterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl, and—O-alkyl-heterocycloalkyl,

or, alternatively, two R⁵ groups bound to the same carbon atom are takentogether with the carbon atom to which they are attached to form acarbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group,an oxime group, or a substituted oxime group, said oxime substituentsbeing independently selected from alkyl, haloalkyl, hydroxyl-substitutedalkyl, and cycloalkyl;

each R⁶ is independently selected from:

(1d) hydrogen, —CHO,

(2d) cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl, —S(O)-cycloalkyl,—S(O)₂-cycloalkyl,

(3d) heterocycloalkyl, —C(O)-heterocycloalkyl, —CO₂-heterocycloalkyl,—S(O)-heterocycloalkyl, —S(O)₂-heterocycloalkyl,

(4d) cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,

(5d) heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl,

(6d) alkyl, —C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl, —S(O)₂-alkyl,

(7d) heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S(O)-heteroalkyl, —S(O)₂-heteroalkyl,

(8d) alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl,

(9d) alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S(O)-alkynyl,—S(O)₂-alkynyl, (10d) aryl, —C(O)-aryl, —CO₂-aryl, —S(O)-aryl,—S(O)₂-aryl,

(11d) heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl,

each R⁷ is independently selected from:

(1e) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO,

(2e) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl,

(3e) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl,

(4e) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl,

(5e) heterocycloalkenyl, —O-heterocycloalkenyl,—C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl, —N(R⁶)-heterocycloalkenyl,—C(O)—N(R²¹)-heterocycloalkenyl, —N(R²¹)—C(O)-heterocycloalkenyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl, —N(R²¹)—S(O)-heterocycloalkenyl,—N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl,

(6e) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7e) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl,

(8e) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl,

(9e) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R⁶)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl,

(10e) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl, —S(O)₂—N(R²¹)-aryl,

(11e) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl, —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R⁷ may be connected throughany available carbon or heteroatom,

each R¹¹ is independently selected from H and lower alkyl;

each R¹² is independently selected from H, lower alkyl, —OH,hydroxy-substituted lower alkyl;

each R¹³ is independently selected from H, unsubstituted lower alkyl,lower alkyl substituted with one or more groups each independentlyselected from hydroxyl and alkoxy, or R¹² and R¹³ are taken together toform an oxo; and

each R¹⁴ is independently selected from H and fluoro.

In one embodiment of the invention, each V is independently selectedfrom the group consisting of: alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, cycloalkenyl, aryl, and heteroaryl,

wherein said heterocycloalkyl and heteroaryl are connected through acarbon atom, and

wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,aryl, and heteroaryl of V are unsubstituted or substituted with one ormore groups independently selected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano, —CHO;

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl;

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl;

(4) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)— cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl;

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl, and—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl;

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl;

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl;

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl;

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl;

(10) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl;

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl;

wherein said heteroalkyl of (7), heterocycloalkyl of (3),heterocycloalkenyl of (5), and heteroaryl of (11) are connected throughany available carbon atom or heteroatom, and

wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenyl of(1) through (11) are unsubstituted or substituted with one or moregroups independently selected from R².

In another embodiment of the invention, each V is independently selectedfrom the group consisting of: alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl,

wherein said heterocycloalkyl, and heteroaryl of V are connected througha carbon atom, and

wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylof V are unsubstituted or substituted with one or more groupsindependently selected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO;

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl;

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl;

(4) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl;

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl;

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl;

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl;

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl;

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl, and —S(O)₂—N(R²¹)-alkynyl;

(10) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl;

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl;

wherein said heteroalkyl of (7), heterocycloalkyl of (3),heterocycloalkenyl of (5), and said heteroaryl of (11) are connectedthrough any available carbon or heteroatom, and

wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenyl of(1) through (11) are unsubstituted or substituted with one or moregroups independently selected from R².

In another embodiment of the invention, each V is independently selectedfrom the group consisting of: alkyl and cycloalkyl, each beingunsubstituted or substituted with one to three groups independentlyselected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO;

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl;

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl;

(4) cycloakenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,—N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl;

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl;

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl;

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl;

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl;

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl;

(10) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl;

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl of (7), heterocycloalkyl of (3),heterocycloalkenyl of (5), and heteroaryl of (11) are connected throughany available carbon atom or heteroatom;

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenyl of(1) through (11) are unsubstituted or substituted with one or moregroups independently selected from R².

In another embodiment of the invention, each V is independently selectedfrom the group consisting of: alkyl unsubstituted or substituted withone to three groups independently selected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO;

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl;

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl;

(4) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)— cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl;

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl, and—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl;

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl;

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl;

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl;

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl;

(10) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl;

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl of (7), heterocycloalkyl of (3),heterocycloalkenyl of (5), and heteroaryl of (11) are connected throughany available carbon or heteroatom, and

wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenyl of(1) through (11) are unsubstituted or substituted with one or moregroups independently selected from R².

In another embodiment, each V is independently selected from the groupconsisting of: C₁₋₆alkyl and cycloalkyl.

In one embodiment of the invention, G is selected from the groupconsisting of:

(1a) hydrogen, halo, —NH₂, —OH, CO₂H and cyano;

(2a) cycloalkyl, —O-cycloalkyl and —N(R¹)-cycloalkyl;

(3a) heterocycloalkyl, —O-heterocycloalkyl and —N(R¹)-heterocycloalkyl;

(6a) alkyl, —O-alkyl and —N(R¹)alkyl;

(7a) heteroalkyl, —O-heteroalkyl and —N(R¹)-heteroalkyl;

(8a) alkenyl, —O-alkenyl and —N(R¹)-alkenyl,

(9a) alkynyl, —O-alkynyl and —N(R¹)-alkynyl;

(10a) aryl, —O-aryl, —C(O)-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl,—N(R¹)-aryl and —C(O)—N(R²¹)-aryl;

(11a) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —S-heteroaryl,—S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl and—C(O)—N(R²¹)-heteroaryl;

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of G areconnected through any available carbon or heteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,said heteroaryl, alkenyl, and alkynyl of G are unsubstituted orsubstituted with one or more groups independently selected from R².

In another embodiment of the invention, G is selected from the groupconsisting of:

(1a) hydrogen;

(2a) cycloalkyl and —N(R¹)-cycloalkyl;

(3a) heterocycloalkyl and —N(R¹)-heterocycloalkyl;

(6a) alkyl and —N(R¹)-alkyl;

(7a) heteroalkyl and —N(R¹)-heteroalkyl;

(8a) alkenyl and —N(R¹)-alkenyl;

(10a) aryl and —N(R¹)-aryl;

(11a) heteroaryl and —N(R¹)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl and heteroaryl of G areconnected through any available carbon or heteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl and alkenyl of G are unsubstituted or substituted with one ormore groups independently selected from R².

In another embodiment of the invention, G is selected from the groupconsisting of:

(1a) hydrogen;

(2a) cycloalkyl and —N(R¹)-cycloalkyl;

(3a) heterocycloalkyl;

(6a) alkyl;

(10a) aryl, and

(11a) heteroaryl,

wherein said heterocycloalkyl, and heteroaryl of G are connected throughany available carbon or heteroatom,

and wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, of G are unsubstituted or substituted with one to threegroups independently selected from R².

In another embodiment, G represents a phenyl group optionallysubstituted with 1-3 groups selected from halo, C₁₋₃alkyl, C₁₋₃alkoxy,haloC₁₋₃alkyl and haloC₁₋₃alkoxy, or with a phenyl ring optionallysubstituted with 1-3 halo atoms.

In the various embodiments of the compounds of the invention describedherein, functional groups for L¹ are to be read from left to rightunless otherwise stated.

In another embodiment of the invention, L¹ is selected from the groupconsisting of —N(R⁴)—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—N(R⁴)—,—O—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—O—, and—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—.

In another embodiment of the invention, L¹ is selected from the groupconsisting of —(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—N(R⁴)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—O— and—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—.

In another embodiment of the invention, L¹ represents—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—.

In another embodiment, L¹ is selected from the group consisting of abond, —NH—(CH₂)₂—, —O—(CH₂)₂—, —O—, —NH—, —N(CH₃)—, —CH₂—,—CH(C₁₋₆alkyl)- and —CH(C₃₋₆cycloalkyl)-.

In another embodiment, L¹ is selected from the group consisting of:—CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH(CH₂CH₂CH₂CH₃)—, —CH(CH(CH₃)₂)—,—CH(cyclopropyl)- and —CH(CH₂CH₂(CH₃)₂)—.

In another embodiment, L¹ is selected from the group consisting of:—CH(cycloalkylalkyl)- and —CH(heterocycloalkylalkyl)-.

In another embodiment, L¹ is —C(R^(5A))₂—, wherein each R^(5A) isindependently selected from the group consisting of H, lower alkyl,haloalkyl, heteroalkyl, cyano-substituted lower alkyl,hydroxy-substituted lower alkyl, cycloalkyl, -alkylcycloalkyl,heterocycloalkyl and -alkylheterocycloalkyl.

In another embodiment, L¹ is —CH(R^(5A))—, wherein R^(5A) is selectedfrom the group consisting of H, lower alkyl, haloalkyl, heteroalkyl,cyano-substituted lower alkyl, hydroxy-substituted lower alkyl,cycloalkyl, -alkylcycloalkyl, heterocycloalkyl, and-alkylheterocycloalkyl.

In another embodiment, L¹ is selected from the group consisting of:

and —(CH₂)₁₋₃—.

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

and —(CH₂)₁₋₃—.

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, L¹ is selected from the group consisting of:

In another embodiment, ring B is phenyl.

In another embodiment, ring B is a phenyl ring wherein the -L¹- and the—C(O)N(R³)Z moieties shown in the formula are bound to said phenyl ringin a 1,4-relationship, and wherein said phenyl ring is (in addition tothe -L¹- and —C(O)N(R³)—Z moieties shown) optionally further substitutedwith one or more substituents R^(a), wherein each R^(a) (when present)is independently selected from the group consisting of halo, alkyl, andhaloalkyl.

In another embodiment, ring B is phenyl which, in addition to themoieties and —C(O)N(R³)—Z shown in the formula, is further substitutedwith one or more independently selected R^(a) groups.

In another embodiment, ring B is a phenyl which, in addition to themoieties L¹- and —C(O)N(R³)—Z shown in the formula, is furthersubstituted with from 1 to 2 substituents, each independently selectedfrom halo, alkyl, and haloalkyl.

In another embodiment, ring B is a 5-6 membered heteroaromatic ringhaving from 1 to 3 ring heteroatoms independently selected from N, O,and S, wherein said ring B is not further substituted.

In one embodiment, ring B is a 5-membered heteroaromatic ring havingfrom 1 to 3 ring heteroatoms independently selected from N, O, and S,wherein said ring B is further substituted with one or moresubstituents. Said further substituents in such embodiments may be boundto one or more available ring carbon atoms and/or ring nitrogen atoms.

In another embodiment, ring B is a 5-membered heteroaromatic ringcontaining from 1 to 3 ring heteroatoms independently selected from N,O, and S, wherein the -L¹- and the —C(O)N(R³)—Z moieties shown in theformula are bound to said 5-membered ring in a 1,3-relationship, andwherein said 5-membered heteroaromatic ring is (in addition to the -L¹-and —C(O)N(R³)—Z moieties shown) optionally further substituted with oneor more substituents R^(a), wherein each R^(a) (when present) isindependently selected from the group consisting of halo, alkyl, andhaloalkyl.

In one embodiment, ring B is a 5-membered heteroaromatic ring havingfrom 1 to 3 ring heteroatoms independently selected from N, O, and S,wherein said 5-membered heteroaromatic ring is further substituted withfrom 1 to 2 substituents, each substituent being independently selectedfrom halo, alkyl, and haloalkyl. In one such embodiment, ring B containstwo said substituents. In another such embodiment, ring B contains onesaid substitutent.

In one embodiment, ring B is a 5-membered heteroaromatic ring, selectedfrom the group consisting of: furan, thiophene, pyrrole, imidazole,pyrazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiadiazole,oxazole, oxadiazole, and isoxazole, each of which may be optionallyfurther substituted as described herein. Non-limiting examples of ring B(shown connected to moieties L¹ and —C(O)—N(R³)—Z) include:

wherein each ring B shown is optionally further substituted on anavailable ring carbon atom or ring nitrogen atom with one or more groupsR^(a), wherein each R^(a), when attached to a ring carbon atom, isindependently selected from halo, alkyl, and haloalkyl, and wherein eachR^(a), when attached to a ring nitrogen atom, is independently selectedfrom alkyl, and haloalkyl. Non-limiting examples of such groupssubstituted on an available ring nitrogen atom include:

In one embodiment, ring B is a 6-membered heteroaromatic ring havingfrom 1 to 3 ring nitrogen atoms, wherein said ring B is not furthersubstituted.

In one embodiment, ring B is a 6-membered heteroaromatic ring havingfrom 1 to 3 ring nitrogen atoms wherein said ring B is furthersubstituted with one or more substituents. Said further substituents insuch embodiments may be bound to one or more available ring carbon atomsand/or ring nitrogen atoms.

In another embodiment, ring B is a 6-membered heteroaromatic ringcontaining from 1 to 3 ring nitrogen atoms, wherein the -L¹- and the—C(O)N(R³)—Z moieties shown in the formula are bound to said 6-memberedring in a 1,4-relationship, and wherein said 6-membered heteroaromaticring is (in addition to -L¹- and —C(O)N(R³)Z moieties shown) optionallyfurther substituted with one or more substituents R^(a), wherein eachR^(a) (when present) is independently selected from the group consistingof halo, alkyl, and haloalkyl.

In another embodiment, ring B is a 6-membered heteroaromatic ring havingfrom 1 to 3 ring nitrogen atoms, wherein said ring B is furthersubstituted with from 1 to 3 substituents, each substituent beingindependently selected from halo, alkyl, and haloalkyl. In one suchembodiment, ring B contains three said substituents. In one suchembodiment, ring B contains two said substituents. In another suchembodiment, ring B contains one said substitutent.

In another embodiment, ring B is a 5-6 membered heteroaromatic ringselected from the group consisting of: thiophene, pyridine, pyrimidine,pyrazine, pyridazine, and triazine, each of which may be optionallyfurther substituted as described herein. Non-limiting examples of ring B(shown connected to moieties L¹ and —C(O)—N(R³)—Z) include

wherein any of such moieties may be optionally further substituted withone or more groups R^(a), wherein each R^(a) is independently selectedfrom halo, alkyl, and haloalkyl.

In another embodiment R³ is H.

In another embodiment R³ is selected from methyl, ethyl, n-propyl andisopropyl.

In another embodiment Z is a moiety selected from the group consistingof: —(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH, —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH,—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)Oalkyl,—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)Oalkyl and

In another embodiment Z is a moiety selected from the group consistingof: —(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH, —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH,—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)Oalkyl and—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)Oalkyl.

In another embodiment, Z is —(C(R¹¹)₂)—(C(R¹²)(R¹³))_(m)—C(O)OH.

Pharmaceutically acceptable salts of such acids are also contemplated asbeing within the scope of the invention. Thus, in another embodiment, Zis —(C(R¹¹)₂)—(C(R¹²)(R¹³))_(m)—C(O)O⁻Na⁺. Additional non-limiting saltscontemplated as alternatives to the sodium salt are known to those ofordinary skill in the art and/or are as described herein.

In another embodiment, Z is —CH₂—(CH(CH₃))C(O)OH.

In another embodiment, Z is —CH₂CH₂—(CH₂)C(O)OH.

In another embodiment, Z is —CH₂—C(CH₃)₂C(O)OH.

In another embodiment, Z is —CH₂—C(CH₃)(OH)C(O)OH.

In another embodiment, Z is —CH₂CH₂C(O)OH.

In another embodiment, Z is —CH₂—CH(OH)C(O)OH.

In another embodiment, Z is —CH(CH₃)—CH₂C(O)OH.

In another embodiment, Z is —C(CH₃)₂—CH₂C(O)OH.

In another embodiment, Z is —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH.

In another embodiment, Z is —CH₂CH(F)C(O)OH.

In another embodiment, Z is —CH₂CF₂C(O)OH.

In another embodiment, Z is —CH(CH₃)CF₂C(O)OH.

In another embodiment, Z is —CH₂CH₂CF₂C(O)OH.

In another embodiment, Z is

In another embodiment, Z is

In another embodiment, Z is

In another embodiment when Z is a moiety selected from—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH, or —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH,the —C(O)OH group may be replaced by a moiety -Q, wherein Q is selectedfrom the group consisting of:

Such moieties Q are readily available to those skilled in the art andmay be made, for example, by methods according to Stensbol et al., J.Med. Chem., 2002, 45, 19-31, or according to Moreira Lima et al.,Current Med. Chem., 2005, 12, 23-49.

As indicated above, tautomers of the compounds of the various formulasof the invention described herein are embraced by the present invention.For example, it shall be understood that tetrazoles (such as thosedescribed in variable “Z”) written as:

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, —(C(R⁵)₂)_(s)— is selected from the groupconsisting of —(C(CH₃)₂)_(s)—, —(CH(CH₃))_(s)—, and —(CH₂)_(s)—, whereins is 1-3.

In another embodiment, —(C(R⁵)₂)_(s)— is selected from the groupconsisting of —(C(CH₃)₂)_(s)—, —(CH(CH₃))_(s)—, and —(CH₃)_(s)—, whereins is 1-2.

In another embodiment, —(C(R⁵)₂)_(s)— is selected from the groupconsisting of —(C(CH₃)₂)_(s)—, —(CH(CH₃))_(s)—, and —(CH₂)_(s)—, whereins is 1.

In another embodiment, —(C(R⁵)₂)_(s)— is selected from the groupconsisting of —(CH(CH₃))_(s)— and —(CH₂)_(s)—, wherein s is 1.

In another embodiment, —(C(R⁵)₂)_(s)— is —(CH(CH₃))—.

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl,

(4b) cycloalkenyl,

(6b) alkyl, —C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl and —S(O)₂-alkyl,

(7b) heteroalkyl,

(8b) alkenyl,

(9b) alkynyl,

(10b) aryl,

(11b) heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of R¹ may beconnected through any available carbon or heteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, said alkenyl, said alkynyl, said cycloalkenyl, and saidheterocycloalkenyl of R¹ are unsubstituted or substituted with one ormore groups independently selected from R².

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl,

(6b) alkyl,

(7b) heteroalkyl,

(8b) alkenyl,

(10b) aryl,

(11b) heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of R¹ may beconnected through any available carbon or heteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryland heteroaryl of R¹ are unsubstituted or substituted with one to threegroups independently selected from R².

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen, and

(6b) alkyl, said alkyl being unsubstituted or substituted with one tothree groups independently selected from R².

In another embodiment, each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, cyano and —CHO,

(2c) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl and —N(R²¹)—C(O)-cycloalkyl,

(3c) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl and —N(R²¹)—C(O)-heterocycloalkyl,

(4c) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl and—N(R²¹)—C(O)-cycloalkenyl,

(5c) heterocycloalkenyl, —O-heterocycloalkenyl,—C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl, —N(R⁶)-heterocycloalkenyl,—C(O)—N(R²¹)-heterocycloalkenyl, and —N(R²¹)—C(O)-heterocycloalkenyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl, —S(O)₂—N(R²¹)-alkyl,

(7c) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl and—N(R²¹)—C(O)-heteroalkyl,

(8c) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl and—N(R²¹)—C(O)-alkenyl,

(9c) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R²¹)-alkynyl and—N(R²¹)—C(O)-alkynyl,

(10c) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl and —N(R²¹)—C(O)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl and —N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R² may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R² areunsubstituted or substituted with one or more groups independentlyselected from R⁷.

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl,

(4b) cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,

(6b) alkyl, —C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl, —S(O)₂-alkyl,

(7b) heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S(O)-heteroalkyl, —S(O)₂-heteroalkyl,

(8b) alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl,

(9b) alkynyl,

(10b) aryl, —C(O)-aryl, —CO₂-aryl,

(11b) heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R¹ may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R¹ areunsubstituted or substituted with one or more groups independentlyselected from R².

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl,

(6b) alkyl,

(7b) heteroalkyl,

(8b) alkenyl,

(10b) aryl, and

(11b) heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R¹ may be connected through any available carbon orheteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl of R¹ are unsubstituted or substituted with one to threegroups independently selected from R².

In another embodiment, each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl, and

(6b) alkyl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R¹ may be connected through any available carbon orheteroatom,

and wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl of R¹ are unsubstituted or substituted with one to threegroups independently selected from R².

In another embodiment each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H and CO₂H,

(2c) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R⁶)-cycloalkyl and —N(R⁶)—C(O)-cycloalkyl,

(3c) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl and —N(R²¹)—C(O)-heterocycloalkyl,

(4c) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl and—N(R²¹)—C(O)-cycloalkenyl,

(5c) heterocycloalkenyl, —O-heterocycloalkenyl,—C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S-heterocycloalkenyl, —S(O)-heterocycloalkenyl,—S(O)₂-heterocycloalkenyl, —N(R⁶)-heterocycloalkenyl,—C(O)—N(R²¹)-heterocycloalkenyl, and —N(R²¹)—C(O)-heterocycloalkenyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl and —S(O)—N(R²¹)-alkyl, —S(O)₂—N(R²¹)-alkyl,

(7c) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl and—N(R²¹)—C(O)-heteroalkyl,

(8c) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl and—N(R²¹)—C(O)-alkenyl,

(9c) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R²¹)-alkynyl and—N(R²¹)—C(O)-alkynyl,

(10c) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl, —S(O)₂—N(R²¹)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl,

wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R² may be connected throughany available carbon or heteroatom,

and wherein said alkyl, said heteroalkyl, said cycloalkyl, saidheterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R² areunsubstituted or substituted with one or more groups independentlyselected from R⁷.

In another embodiment each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H and CO₂H,

(2c) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —S-cycloalkyl and—N(R⁶)-cycloalkyl,

(3c) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—S-heterocycloalkyl, —S(O)-heterocycloalkyl, —S(O)₂-heterocycloalkyl and—N(R⁶)-heterocycloalkyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7c) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl and —S-heteroalkyl,

(8c) alkenyl, —O-alkenyl and —C(O)-alkenyl,

(10c) aryl, —O-aryl, —C(O)-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl,—N(R⁶)-aryl, —C(O)—N(R²¹)-aryl and —N(R²¹)—C(O)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl and —N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R² may be connected through any available carbon orheteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, and said heterocycloalkenyl of R² are unsubstitutedor substituted with one to three groups independently selected from R⁷.

In another embodiment each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H and CO₂H,

(2c) cycloalkyl,

(3c) heterocycloalkyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —S-alkyl, —S(O)₂-alkyl, —N(R⁶)-alkyl,—C(O)—N(R²¹)-alkyl and —N(R²¹)—C(O)-alkyl,

(7c) heteroalkyl and —O-heteroalkyl,

(8c) alkenyl,

(10c) aryl, —O-aryl and —C(O)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —S-heteroaryl,—S(O)₂-heteroaryl, —N(R⁶)-heteroaryl, —C(O)—N(R²¹)-heteroaryl and—N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R² may be connected through any available carbon orheteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, and said heterocycloalkenyl of R² are unsubstitutedor substituted with one to three groups independently selected from R⁷.

In another embodiment, each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H and cyano,

(2c) cycloalkyl,

(3c) heterocycloalkyl,

(6c) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,

(7c) heteroalkyl,

(10c) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl and —N(R²¹)—C(O)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl and —N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of R² may beconnected through any available carbon or heteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl of R² are unsubstituted or substituted with one to threegroups independently selected from R⁷.

In another embodiment, R³ is H.

In another embodiment, R³ is selected from the group consisting ofmethyl, ethyl, n-propyl, and isopropyl.

In another embodiment, Z is —(C(R¹¹)₂)—(C(R¹²)(R¹³))_(m)—C(O)OH.

In another embodiment, Z is —(CH₂)—(CH(CH₃))—C(O)OH.

In another embodiment, Z is —(CH₂)—(CH₂)—(CH₂)—C(O)OH.

In another embodiment, Z is —(CH₂)—C(CH₃)₂—C(O)OH.

In another embodiment, Z is —(CH₂)—C(CH₃)(OH)—C(O)OH.

In another embodiment, Z is —CH₂—CH₂—C(O)OH.

In another embodiment, Z is —CH₂—CH(OH)—C(O)OH.

In another embodiment, Z is —CH(CH₃)—CH₂—C(O)OH.

In another embodiment, Z is —C(CH₃)₂—CH₂—C(O)OH.

In another embodiment, Z is —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—, —C(O)OH.

In another embodiment, Z is —CH₂—CH(F)—C(O)OH.

In another embodiment, Z is —CH₂—CF₂—C(O)OH.

In another embodiment, Z is —CH(CH₃)—CF₂—C(O)OH.

In another embodiment, Z is —CH₂—CH₂—CF₂—C(O)OH.

In another embodiment, Z is

In another embodiment, Z is

In another embodiment, Z is

In another embodiment, each R⁶ is independently selected from:

(1d) hydrogen,

(2d) cycloalkyl,

(3d) heterocycloalkyl,

(6d) alkyl, and

(7d) heteroalkyl,

In another embodiment, each R⁷ is independently selected from:

(1e) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO,

(2e) cycloalkyl and —O-cycloalkyl,

(3e) heterocycloalkyl,

(6e) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl and —N(R²¹)—C(O)-alkyl,

(7e) heteroalkyl,

(10e) aryl, —O-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R⁶)-aryl, —C(O)—N(R²¹)-aryl and —N(R²¹)—C(O)-aryl,

(11e) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl and —N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of R⁷ may beconnected through any available carbon or heteroatom.

In another embodiment, each R¹¹ is independently selected from H andC₁₋₃ alkyl.

In another embodiment, each R¹² is independently selected from H andC₁₋₃ alkyl, and hydroxy-substituted C₁₋₃ alkyl;

In another embodiment, each R¹³ is independently selected from H,unsubstituted C₁₋₃ alkyl, C₁₋₃ alkyl substituted with hydroxyl or C₁₋₃alkoxy.

In another embodiment, each R¹⁴ is H.

In another embodiment, Q is a moiety selected from the group consistingof:

wherein each R¹⁰ is independently H or C₁₋₃ alkyl.

In another embodiment, m is an integer from 0 to 2.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, m is 2.

In another embodiment, n is an integer from 0 to 2.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, p is an integer from 0 to 2,

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, p is 2.

In another embodiment, each R⁴ is independently selected from the groupconsisting of: H, —OH, C₁₋₃ alkyl, haloC₁₋₃alkyl, C₁₋₃alkoxy,heteroalkyl, cyano-substituted C₁₋₃alkyl, hydroxy-substituted C₁₋₃alkyl,C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocycloalkyl,—O-heterocycloalkyl, and —O—C₁₋₃alkyl-heterocycloalkyl.

In another embodiment, each R^(5A) is independently selected from H,C₁₋₃ alkyl, haloC₁₋₃alkyl, heteroalkyl, cyano-substituted C₁₋₃alkyl,hydroxy-substituted C₁₋₃alkyl, C₃₋₆cycloalkyl,C₁₋₃-alkyl-C₃₋₆-cycloalkyl, and heterocycloalkyl,—C₁₋₃alkyl-heterocycloalkyl.

In another embodiment, two R^(5A) groups are taken together with thecarbon atom to which they are attached to form a carbonyl group, aspiroC₃₋₆cycloalkyl group, a spiroheterocycloalkyl group, an oximegroup, or a substituted oxime group (said oxime substituents beingindependently selected from haloC₁₋₃alkyl, hydroxyl-substitutedC₁₋₃alkyl and C₃₋₆cycloalkyl).

In another embodiment, each R⁵ is independently selected from H, —OH,C₁₋₃alkyl, haloC₁₋₃alkyl, C₁₋₃alkoxy, heteroalkyl, cyano-substitutedC₁₋₃alkyl, hydroxy-substituted C₁₋₃alkyl, C₃₋₆cycloalkyl,C₁₋₃alkyl-C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,—O—C₁₋₃alkyl-C₃₋₆cycloalkyl, and heterocycloalkyl,—C₁₋₃alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O—C₁₋₃alkyl-heterocycloalkyl.

In another embodiment, two R⁵ groups bound to the same carbon atom aretaken together with the carbon atom to which they are attached to form acarbonyl group, a spiroC₃₋₆cycloalkyl group, a spiroheterocycloalkylgroup, an oxime group, or a substituted oxime group (said oximesubstituents being independently selected from C₁₋₃alkyl, haloC₁₋₃alkyl,hydroxyl-substituted C₁₋₃alkyl and C₃₋₆cycloalkyl).

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, q is 2.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, r is 2.

In another embodiment, s is 0.

In another embodiment, s is 1.

In another embodiment, s is 2.

A subset of compounds of the invention is represented by Formula (A):

and includes pharmaceutically acceptable salts of said compounds,wherein:

each V is independently selected from the group consisting of: alkyl andcycloalkyl, each being unsubstituted or substituted with one to threegroups independently selected from:

(1) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO;

(2) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl;

(3) heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl, and —S(O)₂—N(R²¹)-heterocycloalkyl;

(4) cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl,—S(O)₂-cycloalkenyl, —N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)— cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl;

(5) heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl, and—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl;

(6) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R¹)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl;

(7) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R¹)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl;

(8) alkenyl, —O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl,—S(O)-alkenyl, —S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl;

(9) alkynyl, —O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl,—S(O)-alkynyl, —S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl; —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl;

(10) aryl, —0-aryl, —C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl,—N(R²¹)—C(O)—N(R²¹)-aryl, —N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl,—N(R²¹)—S(O)₂—N(R²¹)-aryl, —S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl;

(11) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl,—S-heteroaryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl;

wherein said heteroalkyl of (7), heterocycloalkyl of (3),heterocycloalkenyl of (5), and heteroaryl of (11) are connected throughany available carbon atom or heteroatom;

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenyl of(1) through (11) are unsubstituted or substituted with one or moregroups independently selected from R²;

G is selected from the group consisting of:

(1a) hydrogen, halo, —NH₂ and —OH;

(2a) cycloalkyl and —N(R¹)-cycloalkyl;

(3a) heterocycloalkyl and —N(R¹)-heterocycloalkyl;

(6a) alkyl and —N(R¹)-alkyl;

(7a) heteroalkyl;

(10a) aryl and —N(R¹)-aryl;

(11a) heteroaryl and —N(R¹)-heteroaryl;

wherein said heterocycloalkyl and heteroaryl of G are connected throughany available carbon or heteroatom,

and wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, of G are unsubstituted or substituted with one to threegroups independently selected from R²;

L¹ represents —(C(R^(5A))₂)—(C(R⁵)₂)_(s)—;

ring B is phenyl;

R³ is H;

Z is selected from the group consisting of:

—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH, —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH,

—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)C(O)Oalkyl,—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)Oalkyl and

each R¹ is independently selected from:

(1b) hydrogen,

(2b) cycloalkyl,

(3b) heterocycloalkyl,

(6b) alkyl,

(7b) heteroalkyl;

(10b) aryl, and

(11b) heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R¹ may be connected through any available carbon orheteroatom,

and wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl of R¹ are unsubstituted or substituted with one to threegroups independently selected from R²;

each R² is independently selected from:

(1c) halo, —NH₂, —OH, —SH, —SO₂H and CO₂H,

(2c) cycloalkyl and —O-cycloalkyl;

(3c) heterocycloalkyl and —O-heterocycloalkyl;

(6e) alkyl and —O-alkyl,

(7c) heteroalkyl and —O-heteroalkyl,

(8c) alkenyl,

(10c) aryl, —O-aryl and —C(O)-aryl,

(11c) heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —S-heteroaryl,—S(O)₂-heteroaryl, —N(R⁶)-heteroaryl, —C(O)—N(R²¹)-heteroaryl and—N(R²¹)—C(O)-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl of R² may be connected through any available carbon orheteroatom,

and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkenyl, and said heterocycloalkenyl of R² are unsubstitutedor substituted with one to three groups independently selected from R⁷;

each R⁷ is independently selected from:

(1e) halo,

(2e) cycloalkyl and —O-cycloalkyl,

(3e) heterocycloalkyl and —O-heterocycloalkyl;

(6e) alkyl and —O-alkyl,

(7e) heteroalkyl and —O-heteroalkyl;

(10e) aryl and —O-aryl,

(11e) heteroaryl and —O-heteroaryl,

wherein said heteroalkyl, heterocycloalkyl, and heteroaryl of R⁷ may beconnected through any available carbon or heteroatom;

each R¹¹ is independently selected from H and C₁₋₃alkyl;

each R¹² is independently selected from H and C₁₋₃alkyl, andhydroxy-substituted C₁₋₃alkyl;

each R¹³ is independently selected from H, unsubstituted C₁₋₃alkyl,C₁₋₃alkyl substituted with hydroxyl and C₁₋₃alkoxy;

each R¹⁴ is H; and p, s, m and n each independently represent 0-2.

Another subset of compounds of the invention is represented by Formula(A):

and includes pharmaceutically acceptable salts of said compounds,wherein:

each V is independently selected from the group consisting of: C₁₋₆alkyland cycloalkyl;

G represents a phenyl group optionally substituted with 1-3 groupsselected from halo, C₁₋₃alkyl, C₁₋₃alkoxy, haloC₁₋₃alkyl andhaloC₁₋₃alkoxy, or with one phenyl ring which is optionally substitutedwith 1-3 halo atoms;

L¹ represents —(C(R^(5A))₂)—(C(R⁵)₂)_(s)—; wherein s is 0-1, each R^(5A)represents H, C₁₋₆alkyl or C₃₋₆cycloalkyl, and when present, each R⁵represents H;

ring B is phenyl;

R³ is H;

Z is selected from the group consisting of: CH₂CH₂CO₂H and

wherein p is 0-2 and when present each R¹¹ is H.

Examples of compounds that are of interest are set forth below in Table1.

TABLE 1

as well as the pharmaceutically acceptable salts thereof.

In the various embodiments described herein, variables of each of thegeneral formulas not explicitly defined in the context of the respectiveformula are as defined in Formula (A).

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

“Mammal” means humans and other mammalian animals.

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a non-human mammal,including, but not limited to, a monkey, baboon, mouse, rat, horse, dog,cat or rabbit. In another embodiment, a patient is a companion animal,including but not limited to a dog, cat, rabbit, horse or ferret. In oneembodiment, a patient is a dog. In another embodiment, a patient is acat.

The term “obesity” as used herein, refers to a patient being overweightand having a body mass index (BMI) of 25 or greater. In one embodiment,an obese patient has a BMI of 25 or greater. In another embodiment, anobese patient has a BMI from 25 to 30. In another embodiment, an obesepatient has a BMI greater than 30. In still another embodiment, an obesepatient has a BMI greater than 40.

The term “impaired glucose tolerance” (IGT) as used herein, is definedas a two-hour glucose level of 140 to 199 mg per dL (7.8 to 11.0 mmol)as measured using the 75-g oral glucose tolerance test. A patient issaid to be under the condition of impaired glucose tolerance when he/shehas an intermediately raised glucose level after 2 hours, wherein thelevel is less than would qualify for type 2 diabetes mellitus.

The term “impaired fasting glucose” (IFG) as used herein, is defined asa fasting plasma glucose level of 100 to 125 mg/dL; normal fastingglucose values are below 100 mg per dL.

The term “effective amount” as used herein, refers to an amount ofCompound of Formula (I) and/or an additional therapeutic agent, or acomposition thereof that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a patient suffering from a Condition. In the combinationtherapies of the present invention, an effective amount can refer toeach individual agent or to the combination as a whole, wherein theamounts of all agents administered are together effective, but whereinthe component agent of the combination may not be present individuallyin an effective amount.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being as describedherein or independently selected from the group consisting of halo,alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy,alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂,—O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl and t-butyl.

The term “haloalkyl” as used herein, refers to an alkyl group, asdefined above, wherein one or more of the alkyl group's hydrogen atomshave been independently replaced with —F, —Cl, —Br or —I. Non-limitingillustrative examples of haloalkyl groups include —CH₂F, —CHF₂, —CF₃,—CH₂CHF₂, —CH₂CF₃, —CCl₃, —CHCl₂, —CH₂Cl, and —CH₂CHCl₂.

“Heteroalkyl” means an alkyl moiety as defined above, having one or morecarbon atoms, for example one, two or three carbon atoms, replaced withone or more heteroatoms, which may be the same or different, where thepoint of attachment to the remainder of the molecule is through a carbonatom of the heteroalkyl radical. Suitable such heteroatoms include O, S,S(O), S(O)₂, and —NH—, —N(alkyl)-. Non-limiting examples include ethers,thioethers, amines, hydroxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl,2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, and the like. Thebond to the parent moiety may be through either an available carbon orheteroatom.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. Further non-limitingexamples of alkylene groups include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂— and —CH₂CH(CH₃)CH₂—. In one embodiment,an alkylene group has from 1 to about 6 carbon atoms. In anotherembodiment, an alkylene group is branched. In another embodiment, analkylene group is linear. More generally, the suffix “ene” on alkyl,aryl, heterocycloalkyl, etc. indicates a divalent moiety, e.g., —CH₂CH₂—is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Alkenylene” means a Bifunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The bond to theparent moiety may be through an available carbon or nitrogen atom.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like. Furthernon-limiting examples of cycloalkyl include the following:

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH— in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc)-, —N(CBz)-, —N(Tos)- group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more “ring system substituents”which may be the same or different, and are as defined herein. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term“oxide,” when it appears in a definition of a variable in a generalstructure described herein, refers to the corresponding N-oxide,S-oxide, or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” Example of such moiety is pyrrolidinone (orpyrrolidone):

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined herein. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidenone (orpyrrolone):

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

It should be understood that for hetero-containing functional groupsdescribed herein, e.g., heterocycloalkyl, heterocycloalkenyl,heteroalkyl, heteroaryl, and arylheterocycloalkyl (e.g., benzo-fusedheterocycloalkyl), the bond to the parent moiety can be through anavailable carbon or heteroatom (e.g., nitrogen atom).

“Arylcycloalkyl” (or “arylfused cycloalkyl”) means a group derived froma fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkylsare those wherein aryl is phenyl (which may be referred to as“benzofused”) and cycloalkyl consists of about 5 to about 6 ring atoms.The arylcycloalkyl can be optionally substituted as described herein.Non-limiting examples of suitable arylcycloalkyls include indanyl (abenzofused cycloalkyl) and 1,2,3,4-tetrahydronaphthyl and the like. Thebond to the parent moiety is through a non-aromatic carbon atom.

“Arylheterocycloalkyl” (or “arylfused heterocycloalkyl”) means a groupderived from a fused aryl and heterocycloalkyl as defined herein.Preferred arylheterocycloalkyls are those wherein aryl is phenyl (whichmay be referred to as “benzofused”) and heterocycloalkyl consists ofabout 5 to about 6 ring atoms. The arylheterocycloalkyl can beoptionally substituted, and/or contain the oxide or oxo, as describedherein. Non-limiting examples of suitable arylfused heterocycloalkylsinclude:

The bond to the parent moiety is through a non-aromatic carbon ornitrogen atom.

It is also understood that the terms “arylfused aryl”, “arylfusedcycloalkyl”, “arylfused cycloalkenyl”, “arylfused heterocycloalkyl”,arylfused heterocycloalkenyl”, “arylfused heteroaryl”, “cycloalkylfusedaryl”, “cycloalkylfused cycloalkyl”, “cycloalkylfused cycloalkenyl”,“cycloalkylfused heterocycloalkyl”, “cycloalkylfusedheterocycloalkenyl”, “cycloalkylfused heteroaryl, “cycloalkenylfusedaryl”, “cycloalkenylfused cycloalkyl”, “cycloalkenylfused cycloalkenyl”,“cycloalkenylfused heterocycloalkyl”, “cycloalkenylfusedheterocycloalkenyl”, “cycloalkenylfused heteroaryl”,“heterocycloalkylfused aryl”, “heterocycloalkylfused cycloalkyl”,“heterocycloalkylfused cycloalkenyl”, “heterocycloalkylfusedheterocycloalkyl”, “heterocycloalkylfused heterocycloalkenyl”,“heterocycloalkylfused heteroaryl”, “heterocycloalkenylfused aryl”,“heterocycloalkenylfused cycloalkyl”, “heterocycloalkenylfusedcycloalkenyl”, “heterocycloalkenylfused heterocycloalkyl”,“heterocycloalkenylfused heterocycloalkenyl”, “heterocycloalkenylfusedheteroaryl”, “heteroarylfused aryl”, “heteroarylfused cycloalkyl”,“heteroarylfused cycloalkenyl”, “heteroarylfused heterocycloalkyl”,“heteroarylfused heterocycloalkenyl”, and “heteroarylfused heteroaryl”are similarly represented by the combination of the groups aryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, andheteroaryl, as previously described. Any such groups may beunsubstituted or substituted with one or more ring system substituentsat any available position as described herein.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl. The term (and similar terms) may bewritten as “arylalkyl-” to indicate the point of attachment to theparent moiety.

Similarly, “heteroarylalkyl”, “cycloalkylalkyl”, “cycloalkenylalkyl”,“heterocycloalkylalkyl”, “heterocycloalkenylalkyl”, etc., mean aheteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, etc. as described herein bound to a parent moietythrough an alkyl group. Preferred groups contain a lower alkyl group.Such alkyl groups may be straight or branched, unsubstituted and/orsubstituted as described herein.

Similarly, “arylfused arylalkyl-”, arylfused cycloalkylalkyl-, etc.,means an arylfused aryl group, arylfused cycloalkyl group, etc. linkedto a parent moiety through an alkyl group. Preferred groups contain alower alkyl group. Such alkyl groups may be straight or branched,unsubstituted and/or substituted as described herein.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Cyanoalkyl” means a NC-alkyl- group in which alkyl is as previouslydefined. Preferred cyanoalkyls contain lower alkyl. Non-limitingexamples of suitable cyanoalkyl groups include cyanomethyl and2-cyanoethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl carbon. Preferred acyls contain a loweralkyl. Non-limiting examples of suitable acyl groups include formyl,acetyl and propanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl carbon. Non-limiting examples of suitable groups includebenzoyl and 1-naphthoyl.

“Heteroaroyl” means an heteroaryl-C(O)— group in which the heteroarylgroup is as previously described. The bond to the parent moiety isthrough the carbonyl carbon. Non-limiting examples of suitable groupsinclude pyridoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” (or “arylalkyloxy”) means an aralkyl-O— group (anarylalkyl-O— group) in which the aralkyl group is as previouslydescribed. Non-limiting examples of suitable aralkyloxy groups includebenzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moietyis through the ether oxygen.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkenyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonylcarbon.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through the carbonylcarbon.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl carbon.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfur atom of the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfur atom of the sulfonyl.

“Spirocycloalkyl” means a cycloalkyl group attached to a parent moietyat a single carbon atom. Non-limiting examples of spirocycloalkylwherein the parent moiety is a cycloalkyl include spiro [2.5] octane,spiro [2.4] heptane, etc. Non-limiting examples of spirocycloalkylwherein the parent moiety is an The alkyl moiety linking fused ringsystems (such as the alkyl moiety in heteroarylfused heteroarylalkyl-)may optionally be substituted with spirocycloalkyl or other groups asdescribed herein. Non-limiting spirocycloalkyl groups includespirocyclopropyl, spriorcyclobutyl, spirocycloheptyl, andspirocyclohexyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁸ in —N(R⁸)₂,or a variable appears more than once in a structure presented hereinsuch as Formula (I), the variables can be the same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.Examples of “one or more” include one to six, one to four, one to three,one or two, and one substituent. With respect to the compositions andmethods comprising the use of “at least one compound of the invention,e.g., of Formula (I),” one to three compounds of the invention, e.g., ofFormula (I) can be administered at the same time, preferably one.

Compounds of the invention may contain one or more rings having one ormore ring system substituents. “Ring system substituent” means asubstituent attached to an aromatic or non-aromatic ring system which,for example, replaces an available hydrogen on the ring system. Ringsystem substituents may be the same or different, each being asdescribed herein or independently selected from the group consisting ofalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl,aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietiesare rings such as heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl rings. Additional non-limitingexamples include methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the likewhich form moieties such as, for example:

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g. containing (R)- and (S)-stereochemistry. For example:

means containing both

The wavy line

as used herein, indicates a point of attachment to the rest of thecompound. For example, each wavy line in the following structure:

indicates a point of attachment to the core structure, as describedherein.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

It is noted that the carbon atoms for compounds of the invention may bereplaced with 1 to 3 silicon atoms so long as all valency requirementsare satisfied.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

In one embodiment, a compound or compounds of the invention is/are inisolated or purified form.

The term “purified” “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1999), Wiley, New York.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of theinvention or a pharmaceutically acceptable salt, hydrate or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of the invention or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of the invention incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N- or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of the invention can form salts which are also within thescope of this invention. Reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof the invention contains both a basic moiety, such as, but not limitedto a pyridine or imidazole, and an acidic moiety, such as, but notlimited to a carboxylic acid, zwitterions (“inner salts”) may be formedand are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of the invention, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the invention (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Suitable hydrogen atoms of the compounds of the invention which may bedeuterated include one or more hydrogen atoms of the lower alkylgroup(s) and/or hydroxyl-substituted lower alkyl groups of R⁵.Additional suitable hydrogen atoms which may be deuterated include, ineach of Formula (A), Formula (I), Formula (III), Formula (IV), Formula(V), and/or Formula (VI), one or more hydrogen atoms of the groups R¹¹,R¹² and/or R¹³ of Z.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention. For example, the term“compounds of formula (A)” as used herein includes the solvates, esters,prodrugs, tautomers and isomers of the depicted genus.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of the invention described above incombination with a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a method forinhibiting glucagon receptors comprising exposing an effective amount ofa compound or a composition comprising a compound of the invention toglucagon receptors. In one embodiment, said glucagon receptors are partof a glucagon receptor assay. Non-limiting examples of such assaysinclude glucagon receptor assays and glucagon-stimulated intracellularcAMP formation assays such as those described herein. In one embodiment,said glucagon receptors are expressed in a population of cells. In oneembodiment, the population of cells is in in vitro. In one embodiment,the population of cells is in ex vivo. In one embodiment, the populationof cells is in a patient.

Methods of Treatment, Compositions, and Combination Therapy

In another embodiment, the present invention provides a method oftreating type 2 diabetes mellitus in a patient in need of such treatmentcomprising administering to said patient a compound of the invention ora composition comprising a compound of the invention in an amounteffective to treat type 2 diabetes mellitus.

In another embodiment, the present invention provides a method ofdelaying the onset of type 2 diabetes mellitus in a patient in need ofsuch treatment comprising administering to said patient a compound ofthe invention or a composition comprising a compound of the invention inan amount effective to delay the onset of type 2 diabetes mellitus.

In another embodiment, the present invention provides a method oftreating hyperglycemia, diabetes, or insulin resistance in a patient inneed of such treatment comprising administering to said patient acompound of the invention, or a composition comprising a compound of theinvention, in an amount that is effective to treat hyperglycemia,diabetes, or insulin resistance.

In another embodiment, the present invention provides a method oftreating non-insulin dependent diabetes mellitus in a patient in need ofsuch treatment comprising administering to said patient an anti-diabeticeffective amount of a compound of the invention or a compositioncomprising an effective amount of a compound of the invention.

In another embodiment, the present invention provides a method oftreating obesity in a patient in need of such treatment comprisingadministering to said patient a compound of the invention or acomposition comprising a compound of the invention in an amount that iseffective to treat obesity.

In another embodiment, the present invention provides a method oftreating one or more conditions associated with Syndrome X (also knownas metabolic syndrome, metabolic syndrome X, insulin resistancesyndrome, Reaven's syndrome) in a patient in need of such treatmentcomprising administering to said patient a compound of the invention ora composition comprising an effective amount of a compound of theinvention in an amount that is effective to treat Syndrome X.

In another embodiment, the present invention provides a method oftreating a lipid disorder in a patient in need of such treatmentcomprising administering to said patient a compound of the invention, ora composition comprising a compound of the invention, in an amount thatis effective to treat said lipid disorder. Non-limiting examples of suchlipid disorders include: dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL, andmetabolic syndrome.

In another embodiment, the present invention provides a method oftreating atherosclerosis in a patient in need of such treatmentcomprising administering to said patient a compound of the invention ora composition comprising a compound of the invention, in an amounteffective to treat atherosclerosis.

In another embodiment, the present invention provides a method ofdelaying the onset of, or reducing the risk of developing,atherosclerosis in a patient in need of such treatment comprisingadministering to said patient a compound of the invention or acomposition comprising a compound of the invention, in an amounteffective to delay the onset of, or reduce the risk of developing,atherosclerosis.

In another embodiment, the present invention provides a method oftreating a condition or a combination of conditions selected fromhyperglycemia, low glucose tolerance, insulin resistance, obesity,abdominal obesity, lipid disorders, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, atherosclerosis, atherosclerosis and its sequelae, vascularrestenosis, pancreatitis, neurodegenerative disease, retinopathy,nephropathy, neuropathy, Syndrome X and other conditions where insulinresistance is a component, in a patient in need thereof, comprisingadministering to said patient a compound of the invention, or acomposition comprising a compound of the invention, in an amount that iseffective to treat said condition or conditions.

In another embodiment, the present invention provides a method ofdelaying the onset of a condition or a combination of conditionsselected from hyperglycemia, low glucose tolerance, insulin resistance,obesity, abdominal obesity, lipid disorders, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis, atherosclerosis and itssequelae, vascular restenosis, pancreatitis, neurodegenerative disease,retinopathy, nephropathy, neuropathy, Syndrome X and other conditionswhere insulin resistance is a component, in a patient in need thereof,comprising administering to said patient a compound of the invention, ora composition comprising a compound of the invention, in an amount thatis effective to delay the onset said condition or conditions.

In another embodiment, the present invention provides a method ofreducing the risk of developing a condition or a combination ofconditions selected from hyperglycemia, low glucose tolerance, insulinresistance, obesity, abdominal obesity, lipid disorders, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis, atherosclerosis and itssequelae, vascular restenosis, pancreatitis, neurodegenerative disease,retinopathy, nephropathy, neuropathy, Syndrome X and other conditionswhere insulin resistance or hyperglycemia is a component, in a patientin need thereof, comprising administering to said patient a compound ofthe invention, or a composition comprising a compound of the invention,in an amount that is effective to reduce the risk of developing saidcondition or conditions.

In another embodiment, the present invention provides a method oftreating a condition selected from type 2 diabetes mellitus,hyperglycemia, low glucose tolerance, insulin resistance, obesity,abdominal obesity, lipid disorders, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, atherosclerosis, atherosclerosis and its sequelae, vascularrestenosis, pancreatitis, neurodegenerative disease, retinopathy,nephropathy, neuropathy, Syndrome X and other conditions where insulinresistance is a component, in a patient in need thereof, comprisingadministering to said patient effective amounts of a compound of theinvention and one or more additional active agents.

Non-limiting examples of such additional active agents include thefollowing:

DPP-IV inhibitors. Non-limiting examples of DPP-IV inhibitors includealogliptin (Takeda), saxagliptin (Brystol-Myers Squibb), sitagliptin(Januvia™, Merck), vildagliptin (Galvus™ Novartis), denagliptin(GlaxoSmithKline), ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos),ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingelheim), SYR-322(Takeda), compounds disclosed in U.S. Pat. No. 6,699,871, MP-513(Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) and combinationsthereof. Non-limiting examples of such combinations include Janumet™, acombination of sitagliptin/metformin HCl (Merck).

Insulin sensitizers. Non-limiting examples of insulin sensitizersinclude PPAR agonists and biguanides. Non-limiting examples of PPARagonists include glitazone and thiaglitazone agents such asrosiglitazone, rosiglitazone maleate (AVANDIA™, GlaxoSmithKline),pioglitazone, pioglitazone hydrochloride (ACTOS™, Takeda), ciglitazoneand MCC-555 (Mitstubishi Chemical Co.), troglitazone and englitazone.Non-limiting example of biguanides include phenformin, metformin,metformin hydrochloride (such as GLUCOPHAGE®, Bristol-Myers Squibb),metformin hydrochloride with glyburide (such as GLUCOVANCE™,Bristol-Myers Squibb) and buformin. Other non-limiting examples ofinsulin sensitizers include PTP-1 B inhibitors; and glucokinaseactivators, such as miglitol, acarbose, and voglibose.

Insulin and insulin mimetics. Non-limiting examples of orallyadministrable insulin and insulin containing compositions include AL-401(Autoimmune), and the compositions disclosed in U.S. Pat. Nos.4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638;5,843,866; 6,153,632; 6,191,105; and International Publication No. WO85/05029, each of which is incorporated herein by reference.

Sulfonylureas and other insulin secretagogues. Non-limiting examples ofsulfonylureas and other secretagogues include glipizide, tolbutamide,glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide,gliclazide, glibenclamide, tolazamide, GLP-1, GLP-1 mimetics, exendin,GIP, secretin, nateglinide, meglitinide, glibenclamide, and repaglinide.Non-limiting examples of GLP-1 mimetics include Byetta™ (exenatide),Liraglutinide, CJC-1131 (ConjuChem), exenatide-LAR (Amylin), BIM-51077(Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compoundsdisclosed in International Publication No. WO 00/07617.

Glucosidase inhibitors and alpha glucosidase inhibitors.

Glucagon receptor antagonists other than compounds of the invention.

Hepatic glucose output lowering agents other than a glucagon receptorantagonist. Non-limiting examples of hepatic glucose output loweringagents include Glucophage and Glucophage XR.

An antihypertensive agent. Non-limiting examples of antihypertensiveagents include beta-blockers and calcium channel blockers (for examplediltiazem, verapamil, nifedipine, amlopidine, and mybefradil), ACEinhibitors (for example captopril, lisinopril, enalapril, spirapril,ceranopril, zefenopril, fosinopril, cilazopril, and quinapril), AT-1receptor antagonists (for example losartan, irbesartan, and valsartan),renin inhibitors and endothelin receptor antagonists (for examplesitaxsentan).

A meglitinide. Non-limiting examples of meglitinides useful in thepresent methods for treating diabetes include repaglinide andnateglinide.

An agent that blocks or slows the breakdown of starches or sugars invivo. Non-limiting examples of antidiabetic agents that slow or blockthe breakdown of starches and sugars in vivo include alpha-glucosidaseinhibitors and certain peptides for increasing insulin production;Alpha-glucosidase inhibitors (which help the body to lower blood sugarby delaying the digestion of ingested carbohydrates, thereby resultingin a smaller rise in blood glucose concentration following meals).Non-limiting examples of alpha-glucosidase inhibitors include acarbose;miglitol; camiglibose; certain polyamines as disclosed in WO 01/47528(incorporated herein by reference); and voglibose.

Peptides for increasing insulin production. Non-limiting examples ofsuitable peptides for increasing insulin production including amlintide(CAS Reg. No. 122384-88-7, Amylin); pramlintide, exendin, certaincompounds having Glucagon-like peptide-1 (GLP-1) agonistic activity asdisclosed in WO 00/07617 (incorporated herein by reference).

A histamine H₃ receptor antagonist. Non-limiting examples of histamineH₃ receptor antagonist agents include the following compound:

A sodium glucose uptake transporter 2 (SGLT-2) inhibitor. Non-limitingexamples of SGLT-2 inhibitors useful in the present methods includedapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095(Tanabe Seiyaku).

PACAP (pituitary adenylate cyclase activating polypeptide agonists) andPACAP mimetics.

Cholesterol lowering agents. Non-limiting examples of cholesterollowering agents include HMG-CoA reducatase inhibitors, sequestrants,nicotinyl alcohol, nicotinic acid and salts thereof, PPAR alphaagonists, PPAR alpha/gamma dual agonists, inhibitors of cholesterolabsorption (such as ezetimibe (Zetia®)), combinations of HMG-CoAreductase inhibitors and cholesterol absorption agents (such asVytorin®), acyl CoA: cholesterol acyltransferase inhibitors,anti-oxidants, LXR modulators, and CETP (cholesterolester transferprotein) inhibitors such as Torcetrapib™ (Pfizer) and Anacetrapib™(Merck).

Agents capable of raising serum HDL cholesterol levels. Non-limitingexamples include niacin (vitamin B-3), such as Niaspan™ (Kos). Niacinmay be administered alone or optionally combined with one or moreadditional active agents such as: niacin/lovastatin (Advicor™, Abbott),niacin/simvastatin (Simcor™, Abbott), and/or niacin/aspirin.

PPAR delta agonists.

Antiobesity agents. Non-limiting examples of anti-obesity agents usefulin the present methods for treating diabetes include a 5-HT2C agonist,such as lorcaserin; a neuropeptide Y antagonist; an MCR4 agonist; an MCHreceptor antagonist; a protein hormone, such as leptin or adiponectin;an AMP kinase activator; and a lipase inhibitor, such as orlistat.

Ileal bile acid transporter inhibitors.

Anti-inflammatory agents, such as NSAIDs. Non-limiting examples ofNSAIDS include a salicylate, such as aspirin, amoxiprin, benorilate ordiflunisal; an arylalkanoic acid, such as diclofenac, etodolac,indometacin, ketorolac, nabumetone, sulindac or tolmetin; a2-arylpropionic acid (a “profen”), such as ibuprofen, carprofen,fenoprofen, flurbiprofen, loxoprofen, naproxen, tiaprofenic acid orsuprofen; a fenamic acid, such as mefenamic acid or meclofenamic acid; apyrazolidine derivative, such as phenylbutazone, azapropazone,metamizole or oxyphenbutazone; a coxib, such as celecoxib, etoricoxib,lumiracoxib or parecoxib; an oxicam, such as piroxicam, lornoxicam,meloxicam or tenoxicam; or a sulfonanilide, such as nimesulide.

Anti-pain medications, including NSAIDs as discussed above, and opiates.Non-limiting examples of opiates include an anilidopiperidine, aphenylpiperidine, a diphenylpropylamine derivative, a benzomorphanederivative, an oripavine derivative and a morphinane derivative.Additional illustrative examples of opiates include morphine,diamorphine, heroin, buprenorphine, dipipanone, pethidine,dextromoramide, alfentanil, fentanyl, remifentanil, methadone, codeine,dihydrocodeine, tramadol, pentazocine, vicodin, oxycodone, hydrocodone,percocet, percodan, norco, dilaudid, darvocet or lorcet.

Antidepressants. Non-limiting examples of tricyclic antidepressantsuseful in the present methods for treating pain include amitryptyline,carbamazepine, gabapentin or pregabalin.

Protein tyrosine phosphatase-1B (PTP-1B) inhibitors.

CB1 antagonists/inverse agonists. Non-limiting examples of CB1 receptorantagonists and inverse agonists include rimonabant and those disclosedin WO03/077847A2, published Sep. 25, 2003, WO05/000809, published Jan.6, 2005, and WO2006/060461, published Jun. 8, 2006.

In another embodiment, the present invention provides a method oftreating a condition selected from hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, in a patient in need of suchtreatment, comprising administering to the patient a therapeuticallyeffective amount or amounts of a compound of the invention, or acomposition comprising a compound of the invention, and an HMG-CoAreductase inhibitor.

In another embodiment, the present invention provides a method oftreating a condition selected from hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, in a patient in need of suchtreatment, comprising administering to the patient a therapeuticallyeffective amount or amounts of a compound of the invention, or acomposition comprising a compound of the invention, and an HMG-CoAreductase inhibitor, wherein the HMG-CoA reductase inhibitor is astatin.

In another embodiment, the present invention provides a method oftreating a condition selected from hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, in a patient in need of suchtreatment, comprising administering to the patient a therapeuticallyeffective amount or amounts of a compound of the invention, or acomposition comprising a compound of the invention, and an HMG-CoAreductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statinselected from lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, itavastatin, ZD-4522, and rivastatin.

In another embodiment, the present invention provides a method ofreducing the risk of developing, or delaying the onset of, a conditionselected from hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia,in a patient in need of such treatment, comprising administering to thepatient a therapeutically effective amount or amounts of a compound ofthe invention, or a composition comprising a compound of the invention,and an HMG-CoA reductase inhibitor.

In another embodiment, the present invention provides a method ofreducing the risk of developing, or delaying the onset of, a conditionselected from hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia,in a patient in need of such treatment, comprising administering to thepatient a therapeutically effective amount or amounts of a compound ofthe invention, or a composition comprising a compound of the invention,and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductaseinhibitor is a statin.

In another embodiment, the present invention provides a method ofreducing the risk of developing, or delaying the onset of, a conditionselected from hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia,in a patient in need of such treatment, comprising administering to thepatient a therapeutically effective amount or amounts of a compound ofthe invention, or a composition comprising a compound of the invention,and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductaseinhibitor is a statin selected from lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, andrivastatin.

In another embodiment, the present invention provides a method ofreducing the risk of developing, or delaying the onset ofatherosclerosis, high LDL levels, hyperlipidemia, and dyslipidemia, in apatient in need of such treatment, comprising administering to thepatient a therapeutically effective amount or amounts of a compound ofthe invention, or a composition comprising a compound of the invention,and a cholesterol absorption inhibitor, optionally in furthercombination with a statin.

In another embodiment, the present invention provides a method ofreducing the risk of developing, or delaying the onset ofatherosclerosis, high LDL levels, hyperlipidemia, and dyslipidemia, in apatient in need of such treatment, comprising administering to thepatient a therapeutically effective amount or amounts of a compound ofthe invention, or a composition comprising a compound of the invention,and a cholesterol absorption inhibitor, optionally in furthercombination with one or more statins, wherein the cholesterol absorptioninhibitor is selected from ezetimibe, ezetimibe/simvastatin combination(Vytorin®), and a stanol.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising (1) a compound according to the invention; (2)one or more compounds or agents selected from DPP-IV inhibitors, insulinsensitizers, insulin and insulin mimetics, a sulfonylurea, an insulinsecretagogue, a glucosidase inhibitor, an alpha glucosidase inhibitor, aglucagon receptor antagonists other than a compound of the invention, ahepatic glucose output lowering agent other than a glucagon receptorantagonist, an antihypertensive agent, a meglitinide, an agent thatblocks or slows the breakdown of starches or sugars in vivo, analpha-glucosidase inhibitor, a peptide capable of increasing insulinproduction, a histamine H₃ receptor antagonist, a sodium glucose uptaketransporter 2 (SGLT-2) inhibitor, a peptide that increases insulinproduction, a GIP cholesterol lowering agent, a PACAP, a PACAP mimetic,a PACAP receptor 3 agonist, a cholesterol lowering agent, a PPAR deltaagonist, an antiobesity agent, an ileal bile acid transporter inhibitor,an anti-inflammatory agent, an anti-pain medication, an antidepressant,a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, a CB1 antagonist,and a CB1 inverse agonist; and (3) one or more pharmaceuticallyacceptable carriers.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more compounds of the invention isadministered during at time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more compounds of the invention andthe additional therapeutic agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating acondition.

In another embodiment, the one or more compounds of the invention andthe additional therapeutic agent(s) are administered in doses lower thanthe doses commonly employed when such agents are used as monotherapy fortreating a condition.

In still another embodiment, the one or more compounds of the inventionand the additional therapeutic agent(s) act synergistically and areadministered in doses lower than the doses commonly employed when suchagents are used as monotherapy for treating a condition.

In one embodiment, the one or more compounds of the invention and theadditional therapeutic agent(s) are present in the same composition. Inone embodiment, this composition is suitable for oral administration. Inanother embodiment, this composition is suitable for intravenousadministration.

The one or more compounds of the invention and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more compounds of theinvention and the additional therapeutic agent(s) may inhibit theresistance of a condition to the agent(s).

In one embodiment, when the patient is treated for diabetes, a diabeticcomplication, impaired glucose tolerance or impaired fasting glucose,the other therapeutic is an antidiabetic agent which is not a compoundof the invention. In another embodiment, when the patient is treated forpain, the other therapeutic agent is an analgesic agent which is not acompound of the invention.

In another embodiment, the other therapeutic agent is an agent usefulfor reducing any potential side effect of a compound of the invention.Non-limiting examples of such potential side effects include nausea,vomiting, headache, fever, lethargy, muscle aches, diarrhea, generalpain, and pain at an injection site.

In one embodiment, the other therapeutic agent is used at its knowntherapeutically effective dose. In another embodiment, the othertherapeutic agent is used at its normally prescribed dosage. In anotherembodiment, the other therapeutic agent is used at less than itsnormally prescribed dosage or its known therapeutically effective dose.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention of acondition described herein can be determined by the attending clinician,taking into consideration the approved doses and dosage regimen in thepackage insert; the age, sex and general health of the patient; and thetype and severity of the viral infection or related disease or disorder.When administered in combination, the compound(s) of the invention andthe other agent(s) for treating diseases or conditions listed above canbe administered simultaneously or sequentially. This is particularlyuseful when the components of the combination are given on differentdosing schedules, e.g., one component is administered once daily andanother every six hours, or when the preferred pharmaceuticalcompositions are different, e.g. one is a tablet and one is a capsule. Akit comprising the separate dosage forms is therefore advantageous.

Generally, a total daily dosage of the one or more compounds of theinvention and the additional therapeutic agent(s) can, when administeredas combination therapy, range from about 0.1 to about 2000 mg per day,although variations will necessarily occur depending on the target ofthe therapy, the patient and the route of administration. In oneembodiment, the dosage is from about 0.2 to about 100 mg/day,administered in a single dose or in 2-4 divided doses. In anotherembodiment, the dosage is from about 1 to about 500 mg/day, administeredin a single dose or in 2-4 divided doses. In another embodiment, thedosage is from about 1 to about 200 mg/day, administered in a singledose or in 2-4 divided doses. In still another embodiment, the dosage isfrom about 1 to about 100 mg/day, administered in a single dose or in2-4 divided doses. In yet another embodiment, the dosage is from about 1to about 50 mg/day, administered in a single dose or in 2-4 divideddoses. In a further embodiment, the dosage is from about 1 to about 20mg/day, administered in a single dose or in 2-4 divided doses.

As indicated above, in one embodiment, the invention providescompositions comprising an effective amount of one or more compounds ofthe invention or a pharmaceutically acceptable salt, solvate, ester orprodrug thereof, and a pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

In one embodiment, the compound of the invention is administered orally.

In another embodiment, the compound of the invention is administeredparenterally.

In another embodiment, the compound of the invention is administeredintravenously.

In one embodiment, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation is fromabout 0.1 to about 2000 mg. Variations will necessarily occur dependingon the target of the therapy, the patient and the route ofadministration. In one embodiment, the unit dose dosage is from about0.2 to about 1000 mg. In another embodiment, the unit dose dosage isfrom about 1 to about 500 mg. In another embodiment, the unit dosedosage is from about 1 to about 100 mg/day. In still another embodiment,the unit dose dosage is from about 1 to about 50 mg. In yet anotherembodiment, the unit dose dosage is from about 1 to about 10 mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two tofour divided doses.

When the invention comprises a combination of at least one compound ofthe invention and an additional therapeutic agent, the two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising at least one compound ofthe invention and an additional therapeutic agent in a pharmaceuticallyacceptable carrier can be administered. The components of thecombination can be administered individually or together in anyconventional dosage form such as capsule, tablet, powder, cachet,suspension, solution, suppository, nasal spray, etc. The dosage of theadditional therapeutic agent can be determined from published material,and may range from about 1 to about 1000 mg per dose. In one embodiment,when used in combination, the dosage levels of the individual componentsare lower than the recommended individual dosages because of theadvantageous effect of the combination.

Thus, the term “pharmaceutical composition” is also intended toencompass both the bulk composition and individual dosage unitscomprised of more than one (e.g., two) pharmaceutically active agentssuch as, for example, a compound of the present invention and anadditional agent selected from the various the additional agentsdescribed herein, along with any pharmaceutically inactive excipients.The bulk composition and each individual dosage unit can contain fixedamounts of the afore-said “more than one pharmaceutically activeagents”. The bulk composition is material that has not yet been formedinto individual dosage units. An illustrative dosage unit is an oraldosage unit such as tablets, pills and the like. Similarly, theherein-described method of treating a patient by administering apharmaceutical composition of the present invention is also intended toencompass the administration of the afore-said bulk composition andindividual dosage units.

In one embodiment, the components of a combination therapy regime are tobe administered simultaneously, they can be administered in a singlecomposition with a pharmaceutically acceptable carrier.

In another embodiment, when the components of a combination therapyregime are to be administered separately or sequentially, they can beadministered in separate compositions, each containing apharmaceutically acceptable carrier.

The components of the combination therapy can be administeredindividually or together in any conventional dosage form such ascapsule, tablet, powder, cachet, suspension, solution, suppository,nasal spray, etc.

Kits

In one embodiment, the present invention provides a kit comprising aeffective amount of one or more compounds of the invention, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of one or more compounds of the invention, or a pharmaceuticallyacceptable salt or solvate thereof, and an amount of at least oneadditional therapeutic agent described above, wherein the combinedamounts are effective for treating or preventing a condition describedherein in a patient.

When the components of a combination therapy regime are to are to beadministered in more than one composition, they can be provided in a kitcomprising in a single package, one container comprising a compound ofthe invention in pharmaceutically acceptable carrier, and one or moreseparate containers, each comprising one or more additional therapeuticagents in a pharmaceutically acceptable carrier, with the activecomponents of each composition being present in amounts such that thecombination is therapeutically effective.

EXPERIMENTALS

A number of references have been cited herein, the entire disclosures ofwhich are incorporated herein by reference.

Abbreviations used in the experimentals may include the following:

ACN Acetonitrile AcOH Acetic acid Aq Aqueous Bn Benzyl BOCtert-Butoxycarbonyl BOC₂O BOG Anhydride Bu Butyl C. (or ° C.) degreesCelsius Cbz benzyloxycarbonyl DBU 1,8-Diazabicyclo[5.4.0]undec-7- eneDCM Dichloromethane DIPEA Diisopropylethylamine DMAN,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME1,2-dimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide DPPF1,1′-(bis-diphenylphosphino) ferrocene EDCI 1-(3- EDC1-(3-Dimethylaminopropyl)-3- Dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride ethylcarbodiimide hydrochloride EI Electron ionization EqEquivalents Et Ethyl EtOAc Ethyl acetate EtOH Ethanol g grams h, hrhours ¹H proton HATU N,N,N′,N′-Tetramethyl- Hex hexanesO-(7-Azabenzotriazol-1- yl)uronium hexafluorophosphate HOBT1-Hydroxybenzotriazole HOBT•H₂O 1-Hydroxybenzotriazole hydrate HOTSpara-toluene sulfonic HOTS•H₂O para-toluene sulfonic acid acid (see alsoTsOH) hydrate (see also TsOH•H₂O) HMPA hexamethylphosphoramide HPLC Highpressure liquid chromatography IPA isopropanol, 2-propanol LDA lithiumdiisopropylamide M Molar mmol milimolar mCPBA meta-Chloroperoxy MeMethyl benzoic acid MeCN Acetonitrile MeOH Methanol min Minutes mgMilligrams MHZ Megahertz mL (or ml) Milliliter Mol molecular sieves Nnormal sieves NMR Nuclear Magnetic MS Mass Spectroscopy Resonance NBSN-Bromosuccinimide NMM N-Methylmorpholine NMP 1-methyl-2-pyrrolidone ONOvernight PTLC Preparative thin layer PyBrOP Bromo-tris-pyrrolidino-chromatography phosphonium hexafluorophosphate PyBOP (Benzotriazol-1-Pyr Pyridine yloxy)tripyrrolidinophosphonium hexa-fluorophosphate Quantquantitative RT or rt Room temperature sat (or Saturated SFCsupercritical fluid sat. or chromatography sat'd.) sgc Silica gel 60SiO₂ Silica gel chromatography tBOC tert-Butoxycarbonyl t-Bu tert-butylTEA Triethylamine Tf Trifluoromethane sulfonyl TFA Trifluoroacetic acidTHF Tetrahydrofuran TLC Thin layer Ts Toluene sulfonyl chromatographyTsOH para-toluene sulfonic TsOH•H₂O para-toluene sulfonic acid acidhydrateGeneral Experimental Information:

Unless otherwise noted, all reactions are magnetically stirred.

Unless otherwise noted, when ethyl acetate, hexanes, dichloromethane,2-propanol, and methanol are used in the experiments described below,they are Fisher Optima grade solvents.

Unless otherwise noted, when diethyl ether is used in the experimentsdescribed below, it is Fisher ACS certified material and is stabilizedwith BHT. Unless otherwise noted, “concentrated to dryness” meansevaporating the solvent from a solution or mixture using a rotaryevaporator.

Unless otherwise noted, flash chromatography is carried out on an Isco,Analogix, or Biotage automated chromatography system using acommercially available cartridge as the column. Columns may be purchasedfrom Isco, Analogix, Biotage, Varian, or Supelco and are usually filledwith silica gel as the stationary phase.

Microwave chemistry is performed in sealed glass tubes in a Biotagemicrowave oven.

General Synthetic Schemes

The general approach to these types of heterocycles is depicted inScheme I. The Boc-amino acid i can be coupled to an appropriatelysubstituted amine ii using standard conditions to provide amides iii.The BOC group in iii can be removed under acid conditions which provideamino-amides iv. Amino-amides iv can be reacted with acyclic ketones vto provide amino amides such as vi (e.g. microwave mediated—Feliu, L.,Font, D., Soley, R., Tailhades, J., Martinez, J., Amblard, M. ARKIVOC2007, 65; thermal conditions—Gomes, P., Araujo, M. J., Rodrigues, M.,Vale, N., Azevedo, Z., Hey, J., Chanbel, P., Morals, J., Moreira, R.Tetrahedron 2004, 60, 5551 and Cheng, S., Wu, H., Hu. X. Syn. Comm.2007, 37, 297); TsOH mediated cyclization as described herein. The aminointermediates such as vi can be oxidized to the imidazoloneintermediates vii (e.g. Dean, A. W., Porter, R. A., WO 2007014762). Theester in vii can be hydrolyzed to provide the acid viii. The acid can becoupled to amines ix using standard protocols to provide the amides suchas x. One skilled in the art would recognize that there are numerouscoupling conditions for formation of amides.

General experimental procedures for the synthesis of benzamides xiii andxvi from benzoic acid viii are described in Scheme 2 and Scheme 3 below.

Treatment of a suitable amine xi or xiv and a benzoic acid viii with acoupling reagent such as PyBOP and the like in a solvent such as DMF andthe like will provide compounds xii or xv (Scheme 2). Cleavage of thetert-butyl ester present in compound xii with an acid such astrifluoroacetic acid or hydrochloric and the like will afford compoundxiii. Cleavage of the tert-butyl ester present in compound xv with anacid such as trifluoroacetic acid or hydrochloric and the like willafford compound xvi.

In Scheme 3, treatment of a suitable amine xvii or xix and a benzoicacid viii with a coupling reagent such as PyBOP and the like in asolvent such as DMF and the like will provide compounds xx or xviii.Hydrolysis of the methyl ester present in compound xx with an aqueoussolution of a base such as NaOH and the like in a solvent mixture suchas MeOH/THF and the like will afford compound xvi. Hydrolysis of themethyl ester present in compound xviii with an aqueous solution of abase such as NaOH and the like in a solvent mixture such as MeOH/THF andthe like will afford compound xiii.

A general experimental procedure for the synthesis of benzamide xxiifrom benzoic acid viii is described in Scheme 4 below. Treatment of xxi(in its free or acid salt form) and a benzoic acid viii with a couplingreagent such as PyBOP and the like and a base such as iPr₂NEt and thelike in a solvent such as DMF and the like will provide a desiredcompound xxii.

The Boc-glycine xxiii and amine ii can be converted into amides of thetype xxiv using conditions previously outlined in Scheme 1. These can betreated with m-CPBA which can provide oxidized heterocycles such asxxvii. Heterocycles such as xxvii can be treated with Br₂PPh₃ to providebromide analogs of the type xxviii. These intermediates can be reactedwith various organometallic reagents using metal catalysis to furnishalkylated intermediates such as vii. The ester in vii can be hydrolyzedusing conditions outlined in Step 5 of Scheme 1. The intermediate of thetype viii can be processed into compounds such as xiii, xvi, and/or xxiiusing previously outlined conditions (Schemes 2, 3, and 4).

Oxidation of xxvi (prepared according to procedures outlined in Scheme5) to the imidazolone xxix can be accomplished via a two-stepchlorination/elimination approach (Scheme 6). Further oxidation of xxixto xxx can be performed upon treatment of xxix with m-CPBA. Compoundxxxi, wherein X is triflyl can be accessed from compound xxx upontreatment with trifluoromethanesulfonic anhydride and triethylamine.Conversely, compound xxxi, wherein X is chloro can be accessed fromcompound xxx upon treatment with POCl₃ and IPr₂NEt in toluene at reflux.Compounds vii, wherein G is attached to the imidazolone ring through anitrogen, can be prepared via reaction of compounds xxxi with a primaryor secondary, cyclic or acyclic amine in the presence of a base such asiPr₂NEt and the like in a solvent such as MeCN and the like under eitherconventional or microwave heating. Alternatively, palladium-mediatedcoupling between xxxi and a suitable partner such as GB(OH)₂ or GSnBu₃will afford compounds vii, wherein G is aryl or heteroaryl. Hydrolysisof the ester present in compound vii with an aqueous solution of a basesuch as NaOH and the like in a solvent mixture such as MeOH/THF and thelike will afford compound viii. Alternatively, the ester present incompound vii may be cleaved with a reagent such as BBr₃ in a solventsuch as CH₂Cl₂ and the like to provide compound vii. The acid present incompound viii can be converted into compounds such as xiii, xvi, andxxii using conditions previously outlined in Schemes 2, 3, and 4.

A general approach to enantiomerically enriched amines xxxvii andxxxviii is illustrated in Scheme 7. This approach is familiar to oneskilled in the art, and numerous examples exist in the literature (forexample see: Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55,8883-8904). The condensation of the sulfinamide xxxii with aldehydesxxxiii provides the imines xxxiv. Organometallic reagents (such asgrignards: R^(5A)MgBr) add to imines xxxiv to provide diastereomericmixtures of the sulfinamides xxxv and xxxvi. These diastereomers can bepurified by crystallization or chiral HPLC methods that are known tothose skilled in the art. The pure diastereomers xxxv and xxxvi can betreated with HCl to provide the enantiomerically enriched amine HClsalts xxxvii and xxxviii, respectively.

A related approach to these types of enantiomerically enriched amine HClsalts is illustrated in Scheme 8. The condensation of the sulfinamidexxxii with ketones such as xxxix will provide ketimines xl. Imines suchas xl can be reduced (see Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A.J. Org. Chem. 2007, 72, 626) with various reducing reagents to providesulfinamides such as xxv and xxxvi. As previously described, thesesulfinamides can be treated with HCl to provide the enantiomericallyenriched amine HCl salts xxxvii and xxxviii.

A general approach for the synthesis styrenyl imidazolones is summarizedin Scheme 9 below. The nitrone xxvii can undergo a [3+2] cycloadditionwith a styrene substituted with any of the substituents described inFormula A, items (i)-(xiii), as described for substituent G. This willprovide the substituted phenyl isoxazolidine xli. Treatment of xli withaqueous NaOH followed by aqueous HCl will result in the formation of thestyrenyl compounds xlii. These compounds can be processed into compoundssuch as xliii, xliv, and xlv using conditions outlined in Schemes 2, 3,and 4.

Also known to those skilled in the art, are the formation of tetrazoleterminated compounds of the formula xxii via the method outlined inScheme 10. The coupling of acids viii with cyano-substituted alkylamines xivi produces cyanoalkyl-amides of the type xlvii. The cyanogroup in xlvii will react with various reagents, including sodium azidein the presence of an alkyl amine hydrochloride, or sodium azide in thepresence of ZnBr₂ in isopropanol/water to provide compounds xxii.

In an alternative method described in Scheme 11, nitrones such as xxviican be treated with a reagent such as POCl₃ and the like in the presenceof a base such as iPr₂NEt and the like in a solvent such as toluene andthe like to afford the chloroimidazolone xlviii. Treatment of xlviiiwith a primary or secondary amine at temperatures ranging from roomtemperature to 150° C. under either conventional or microwave heatingwill afford compounds vii, wherein G is an amine linked to the corethrough nitrogen. Alternatively, palladium-mediated coupling betweenxlviii and a suitable partner such as GB(OH)₂ or GSnBu₃ will affordcompounds vii, wherein G is aryl or heteroaryl. The ester in vii can behydrolyzed using acidic and/or basic conditions to provide the acidviii. The acid can be converted into compounds xiii, xvi, and xxii usingconditions outlined above in Schemes 2, 3, and 4 wherein G in an aminelinked to the core through the nitrogen.

Alternatively, as described in Scheme 12, one can treat an intermediatesuch as xxx with a coupling reagent such as PyBOP, PyBroP, or BOP-Cl andthe like in the presence of a primary or secondary amine, and a basesuch as iPr₂NEt and the like in a solvent such as MeCN or 1,4-dioxaneand the like to directly prepare compounds vii, wherein G is an aminelinked to the core through nitrogen. The ester in vii can be hydrolyzedusing acidic and/or basic conditions to provide the acid viii. The acidcan be converted into compounds xiii, xvi, and xxii using conditionsoutlined above in Schemes 2, 3, and 4 wherein G in an amine linked tothe core through the nitrogen.

Procedures/Examples

Step 1

The N-Boc amino acid (762 mg, 2.38 mmol), amine HCl salt (746 mg, 2.38mml), PyBop (1.36 g, 2.62 mmol), and iPr₂NEt (922 mg, 7.1 mmol) weretaken up in DCM (30 ml), and the solution was stirred at rt for 18 h.The solution was diluted with DCM and washed with brine. The organiclayer was dried (Na₂SO₄), filtered, and concentrated. The residue waspurified via gradient flash chromatography (0-25% EtOAc in hexanes,SiO₂) which provided the amide as a colorless foam.

Step 2

The amide (1.34 g, 2.3 mmol) and TFA (5 ml) were taken up in DCM (10ml), and the solution was stirred at RT for 3 h. The solution wasconcentrated, and the residue was partitioned between DCM and 1 NNaOH_((aq.)). The aqueous layer was extracted with DCM. The combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated whichprovided the amine as a colorless foam.

Step 3

The amine (540 mg, 1.1 mmol), acetone (1.97 g, 34 mmol), Et₃N (229 mg,2.26 mmol), and 4 A mol sieves (2 g) were taken up in IPA (15 ml), andthe resulting mixture was stirred at reflux (105° C.) for 18 h. Themixture was filtered and concentrated. The residue was purified viagradient flash chromatography (0-50% EtOAc in hexanes, SiO₂) whichprovided the spiro-amine as a colorless foam.

Step 4

The amine (353 mg, 0.68 mmol) was taken up in DCM (10 ml) at rt.tert-Butyl hypochlorite (115 mg, 1.06 mmol) was added to the solution atRT, and the resulting solution was stirred at RT for 20 minutes.Triethylamine (358 mg, 3.54 mmol) was added, and the solution wasstirred at RT for 1 hour. The solution was diluted with DCM and washedwith 10% NaHSO_(3(aq.)). The aqueous layer was extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated.The residue was purified via gradient flash chromatography (0-5% EtOAcin hexanes, SiO₂) which provided the imidazolone-ester as a colorlessoil.

Step 5

The ester (323 mg, 0.62 mmol) was taken up in THF/MeOH (3 ml/3 ml), and2 ml of 2 N NaOH_((aq.)) was added. The solution was stirred at RT for 4h. The solution was concentrated, and the residue was partitionedbetween 1 M HCl_((aq.)) and DCM. The aqueous layer was extracted withDCM. The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated which provided the acid as a colorless foam.

Step 6

The acid (75 mg, 0.16 mold), methyl 3-aminopropanoate HCl (24 mg, 0.17mmol), PyBop (90 mg, 0.17 mmol), and iPr₂NEt (61 mg, 0.47 mmol) weretaken up in DCM (2.5 ml), and the resulting solution was stirred at RTfor 18 h. The solution was diluted with DCM and washed with water. Theaqueous layer was extracted with DCM. The combined organic layers weredried (Na₂SO₄), filtered, and concentrated. The residue was purified viagradient flash chromatography (0-40% EtOAc in hexanes, SiO₂) whichprovided the ester as a colorless foam.

Step 7

The ester (70 mg, 0.12 mmol) was taken up in THF/MeOH (3 ml/3 ml) and 2ml of 2 N NaOH_((aq.)). The solution was stirred at RT for 5 h. Thesolution was concentrated. The residue was acidified with 1 NHCl_((aq.)). The solution was extracted with EtOAc. The combined organiclayers were dried (MgSO₄), filtered, and concentrated. The residue waspurified via reverse phase chromatography (10-80% CH₃CN in _(H2O) with0.1% HCO₂H, C-18) which provided the compound of Example 1 as acolorless solid after evaporation and freeze drying.

The acid (75 mg, 0.16 mmol; prepared according to procedures outlined inScheme A), PyBop (90 mg, 0.17 mmol), iPr₂NEt (61 mg, 0.047 mmol), and(2H-tetrazol-5-yl)methanamine HBr (43 mg, 0.24 mmol) were taken up inDMF (2 ml), and the resulting solution was heated at 70° C. for 1 h. Thesolution was concentrated, and the residue was dissolved in DMSO (3 ml)and loaded onto a reverse phase column (C-18). The sample was elutedusing 10-80% MeOH in H₂O with 0.05 TFA gradient which provided thecompound of Example 2 as a colorless solid after evaporation and freezedrying.

The acid (75 mg, 0.16 mmol; prepared according to procedures outlined inScheme A), PyBop (90 mg, 0.17 mmol), iPr₂NEt (61 mg, 0.047 mmol), and2H-tetrazol-5-amine (20 mg, 0.24 mmol) were taken up in DMF (2 ml), andthe resulting solution was heated at 70° C. for 1 h. The solution wasconcentrated, and the residue was dissolved in DMSO (3 ml) and loadedonto a reverse phase column (C-18). The sample was eluted using 10-80%MeOH in H₂O with 0.05% TFA gradient which provided the compound ofExample 3 as a colorless solid after evaporation and freeze drying.

The compounds of examples 4-16 are made by processes analogous to theSchemes A through D described herein, and are shown in Table 1.

Step 1

2-(tent-Butoxycarbonylamino)-2-(3,5-dichlorophenyl)acetic acid (681 mg,2.13 mmol), (R)-methyl 4-(amino(cyclopropyl)methyl)benzoate HCl (468 mg,1.94 mmol), PyBop (1.11 g, 2.13 mmol), and iPr₂NEt (1.01 mL, 5.82 mmol)were taken up in CH₃CN (20 mL), and the solution was stirred at roomtemperature for 18 hours. The solution was concentrated, and the residuewas partitioned between EtOAc and sat. NaHCO_(3(aq.)). The aqueous layerwas extracted with EtOAc, and the combined organic layers were driedover Na₂SO₄. The mixture was filtered and concentrated which provided ayellow oil. The residue was purified by gradient flash chromatography(ISCO, 0 to 40% EtOAc in hexanes) which provided the amide as a whitesolid.

Step 2

The Boc-amine (1.01 g) was taken up in 20% TFA/DCM (10 mL at roomtemperature. The solution was stirred at room temperature for 18 hours.The solution was concentrated, and the residue was partitioned betweenDCM and 1 N NaOH_((aq.)). The aqueous layer was extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedwhich furnished the amine as a yellow solid.

The free amine (355 mg, 0.87 mmol), 4-tert-butyl-cyclohexanone (270 mg,1.75 mmol) or acetone (254 mg, 4.37 mmol), 4 A mol sieves (350 mg), andEt₃N (0.25 mL) were taken up in MeOH (5 mL). The mixture was heated in amicrowave (130° C., 2 h). The mixture was filtered, and the solution wasconcentrated. The residue was purified via gradient flash chromatography(ISCO, 0-35% EtOAc in hexanes) which furnished the spiro-amine as awhite semi-solid.

To a solution of the spiro-amine (118 mg, 0.26 mmol) in DCM (5 mL), wasadded t-butyl-hypochlorite (38 uL). After 1 hour at room temperature,Et₃N (0.15 mL) was added, and the reaction was stirred at roomtemperature for another 2 hours. The reaction was quenched with aqueousNa₂S₂O₃ solution and extracted with DCM (30 mL×3). The combined organiclayers were concentrated. The residue was used without furtherpurification

The starting material was taken up in 1 N NaOH_((aq.))/dioxane/MeOH(1/1/1, 30 ml total), and the solution was heated at 65° C. for 5 hours.The solution was cooled and stirred at room temperature for 16 hours.The solution was concentrated. The residue was partitioned between DCMand 1 M HCl_((aq.)). The mixture was stirred at room temperature for 0.5h. The layers were separated, and the aqueous layer was extracted withDCM. The combined organic layers were dried (MgSO₄), filtered, andconcentrated which afforded the acid as a white solid.

The acid (125 mg, 0.29 mol), PyBop (229 mg, 0.44 mmol), ^(i)Pr₂NEt (114mg, 0.88 mmol) and beta-alanine tert-butyl ester HCl salt (64 mg, 0.44mmol), were taken up in CH₃CN (10 mL), and the solution was stirred atroom temperature for 18 hours. The solution was concentrated, and theresidue was partitioned between EtOAc and sat. NaHCO₃(aq). The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine and dried (MgSO₄). Filtration and concentration provided ayellow oil. The residue was purified via gradient flash chromatography(ISCO, 0-35% EtOAc in hexanes) which provided the tert-butyl ester as acolorless oil.

The tea-butyl ester (140 mg) was treated with 20% TFA/DCM (5 mL) at roomtemperature for 18 hours. The solution was concentrated and dried underhigh vacuum which provided Example 17.

The bromide was prepared using conditions outlined in Scheme D Steps 1-4using the appropriate amino acid, amine HCl salt, and ketone.

The bromide (136 mg, 0.28 mmol), Pd(PPh₃)₄ (33 mg, 10% mmol), boronicacid (82 mg, 0.43 mmol) and 0.5 mL of aq. NaHCO₃ solution, and 5 mL oftoluene/EtOH (1/1) were placed into a 20 ml vial. The vial was capped,sealed, and heated at 100° C. for 16 hrs. The mixture was diluted withether, filtered through celite, and concentrated. The residue waspurified via gradient flash chromatography (ISCO, 0-40% EtOAc inhexanes) which furnished the desired arylated product.

The arylated product was converted into Example 18 using conditionsoutlined in Scheme D Steps 5-7.

TABLE 1 LCMS Amino Ret Obs. Scheme Ketone acid Amine Ex. LC (min) Ion AK1 A1 M1 1

2 15.5 B 544 B K1 A1 M1 2

2 15.4 B 554 C K1 A1 M1 3

2 16.3 B 540 B K2 A1 M1 4

2 18.7 & 20.0 A 598 C K2 A1 M1 5

2 19.5 & 20.7 B 582 B K2 A2 M1 6

3 17.9 & 19.1 A 548 A K2 A1 M1 7

2 18.9 & 20.2 B 586 A K1 A2 M1 8

2 11.3 A 496 C K1 A2 M1 9

2 12.0 A 492 B K1 A2 M1 10

2 11.2 A 506 A K3 A1 M2 11

4 18.6 A 544 A K2 A1 M2 12

4 12.3 A 476 A K2 A1 M2 13

4 15.5 A 518 A K3 A3 M2 14

4 17.0 A 560 A K3 A4 M2 15

4 16.6 A 544 A K1 A3 M2 16

4 13.1 A 492 D K1 A1 M3 17

1 4.71 A 502 E K1 A5 M4 18

1 7.03 A 594 D K1 A1 M5 19

1 4.93 A 504 D K1 A1 M4 20

1 5.17 A 518 Observed Ion (Obs. Ion) —A— (M + H)⁺; B — (M − H)⁻

Example 17 (120 mg) was dissolved in MeOH (2 mL) at room temperaturefollowed by adding 1.0 eq of NaOH aqueous solution. The solution wasconcentrated and dried under high vacuum which provided the desiredsodium salt Example 1.1.

TABLE 2 Ketone

K1

K2

K3 Amino acid

A1

A2

A3

A4

A5 Amine

M1

M2

M3

M4

M5

LC-1: Column: Gemini C-18, 50×4.6 mm, 5 micron, obtained fromPhenomenex. Mobile phase: A: 0.05% Trifluoroacetic acid in water B:0.05% Trifluofloacetic acid in acetonitrile Gradient: 90:10 to 5:95(A:B) over 5 min. Flow rate: 1.0 mL/min UV detection: 254 nm. ESI-MS:Electro Spray Ionization Liquid chromatography-mass spectrometry(ESI-LC/MS) was performed on a PE SCIEX API-150EX, single quadrupolemass spectrometer.

LC-2: HPLC conditions for the retention time were as follows: Column:Luna C18 100 A, 5 μM: A: 0.025% TFA in water B: 0.025% TFA inacetonitrile: Gradient: 98:2 to 15:85 (A:B) over 5 minutes. Gradient:15:85 to 2:98 over 10 minutes. Hold: 2:98 for 19 minutes followed by a 2minute gradient back to 98:2 (A:B). Flow rate: 1.0 ml/min UV detection:254 nm. Mass spec were obtained by one of the following methods: a)Multimode (ESI and APCI). b) ESI

LC-3: HPLC conditions for the retention time were as follows: Column:Luna C18 100 A, 5 μM: A: 0.025% TFA in water B: 0.025% TFA inacetonitrile: Gradient: 90:10 to 15:85 (A:B) over 5 minutes. Gradient:15:85 to 2:98 over 10 minutes. Hold: 2:98 for 19 minutes followed by a 2minute gradient back to 98:2 (A:B). Flow rate: 1.0 ml/min UV detection:254 nm. Mass spec were obtained by one of the following methods: a)Multimode (ESI and APCI). b) ESI

LC-4: HPLC conditions for the retention time were as follows: Column:Luna C18 100 A, 5 μM: A: 0.025% TFA in water B: 0.025% TFA inacetonitrile: Gradient: 98:2 to 15:85 (A:B) over 10 minutes. Gradient:15:85 to 2:98 over 10 minutes. Hold: 2:98 for 12 minutes followed by a 2minute gradient back to 98:2 (A:B). Flow rate: 1.0 ml/min UV detection:254 nm. Mass spec were obtained by one of the following methods: a)Multimode (ESI and APCI). b) ESI

Biological Assays

The ability of the compounds of the invention to inhibit the binding ofglucagon and their utility in treating or preventing type 2 diabetesmellitus and related conditions can be demonstrated by the following invitro assays.

Glucagon Receptor Binding Assay

Recombinant human glucagon receptor (huGlucR) membranes and mouseglucagon receptor (mGlucR) membranes were prepared in-house fromhuGlucR/clone 103c/CHO and mouse liver tissue, respectively. 0.03 ug/lihuGluR membranes (or 0.5 ug/ml mGlucR) was incubated in assay buffercontaining 0.05 nM ¹²⁵I-Glucagon (Perkin Elmer, NEX 207) and varyingconcentrations of antagonist at room temperature for 60 to 90 (assaybuffer: 50 mM HEPES, 1 mM MgCl2, 1 mM CaCl2, 1 mg/ml BSA, COMPLETEprotease inhibitor cocktail, pH 7.4). The total volume of the assay was200 ul. The assay was performed at room temperature using 96-deep wellplate. Compound 4c, racemic diastereomer 1 (D1), (1.0 μM finalconcentration), described by G. H. Ladouceur et al. in Bioorganic andMedicinal Chemistry Letters, 12 (2002), 3421-3424, was used to determinenon-specific binding. Following incubation, the reaction was stopped byrapid filtration through Unfilter-96 GF/C glass fiber filter plates(Perkin Elmer) pre-soaked in 0.5% polyethyleneimine. The filtrate waswashed using 50 mM Tris-HCl, pH 7.4. Dried filter plates containingbound radioactivity were counted in the presence of scintillation fluid(Microscint 0, Perkin-Elmer) using a Topcount scintillation counter.Data was analyzed using the software program Prism (GraphPad). IC₅₀values were calculated using non-linear regression analysis assumingsingle site competition.

Inhibition of Glucagon-Stimulated Intracellular cAMP Assay

Recombinant human glucagon receptor-expressing CHO cells were harvestedusing a non-enzymatic cell dissociation solution (GIBCO 2672), pelletedand resuspended in stimulation buffer (1×HBSS, 5 mM Hepes, 0.1% BSA,pH7.4 in the presence of proteinase inhibitor and phosphodiesteraseinhibitors). The adenylate cyclase assay was constructed following theLANCE cAMP Kit (Perkin Elmer, AD0264) instructions. Briefly, cells werepreincubated with anti-cAMP antibody and 12 points series dilutedcompound in stimulation buffer with a final concentration of 3% DMSO for30 minutes prior to stimulation with 300 pM glucagon for 45 minutes. Thereaction was stopped by incubating with the supplied detection buffercontaining Europium chelate of the Eu-SA/Biotin-cAMP tracer for 20hours. The assay was done as triplicates in a 384 well plate.Fluorescence at 665 nm was measured using PheraStar instruments. Basalactivity (100% inhibition) was determined using the DMSO control and 0%inhibition was defined as cAMP stimulation produced by 300 pM glucagon.Standard cAMP concentrations were assayed concurrently for conversion offluorescence signal to cAMP level. Data was analyzed using the softwareprogram Prism from GraphPad. IC₅₀ values were calculated usingnon-linear regression analysis assuming single site competition. IC₅₀values for the compounds of the invention shown in the examples measuredless than about 10 μM, in preferred embodiments less than about 1 μM, inmore preferred embodiments less than about 500 nM.

TABLE 2 IC₅₀ Ex. (μM) 1

0.80

3.7 3

6.2 4

1.1 5

5.1 6

3.4 7

0.60 8

4.9 9

5.9 10

8.4 11

1.7 12

1.7 13

4.2 14

5.1 15

3.5 16

8.3 17

1.7 18

1.0 19

1.3 20

2.0

The present invention is not to be limited by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims.

What is claimed is:
 1. A compound represented by Formula (A):

or a pharmaceutically acceptable salt thereof, wherein: L¹ is selectedfrom the group consisting of a bond, —N(R⁴)—,—N(R⁴)—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—N(R⁴)—, —O—,—O—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—O— and—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—, each q is independently an integer from 0to 5; each r is independently an integer from 0 to 3; s is an integerfrom 0 to 5; ring B is a phenyl ring, wherein said phenyl ring is (inaddition to the -L¹- and —C(O)N(R³)—Z moieties shown) optionally furthersubstituted with one or more substituents R^(a), wherein each R^(a)(when present) is independently selected from the group consisting ofhalo, —OH, —SF₅, —OSF₅, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl,alkoxy and —O-haloalkyl, or ring B is a 5-membered heteroaromatic ringcontaining from 1 to 3 ring heteroatoms independently selected from N,O, and S, wherein said 5-membered heteroaromatic ring is (in addition tothe -L¹- and —C(O)N(R³)—Z moieties shown) optionally further substitutedwith one or more substituents R^(a), wherein each R^(a) (when present)is independently selected from the group consisting of halo, —OH, —SF₅,—OSF₅, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy and—O-haloalkyl, or ring B is a 6-membered heteroaromatic ring containingfrom 1 to 3 ring nitrogen atoms, wherein said 6-membered heteroaromaticring is (in addition to -L¹- and —C(O)N(R³)Z moieties shown) optionallyfurther substituted with one or more substituents R^(a), wherein eachR^(a) (when present) is independently selected from the group consistingof halo, —OH, —SF₅, —OSF₅, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and—O-haloalkyl; each V is independently selected from the group consistingof alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein saidheteroalkyl, said heterocycloalkyl, said heterocycloalkenyl, and saidheteroaryl of V may only be connected through carbon, and wherein saidalkyl, said heteroalkyl, said alkenyl, said alkynyl, said cycloalkyl,said heterocycloalkyl, said cycloalkenyl, said heterocycloalkenyl, saidaryl, and said heteroaryl of V are unsubstituted or optionallysubstituted with one or more groups independently selected from: (1)halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO, (2)cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl, (3)heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl, (4)cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,—N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl, (5) heterocycloalkenyl,—O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl, (6) alkyl, —O-alkyl, —C(O)-alkyl,—CO₂-alkyl, —S-alkyl, —S(O)-alkyl, —S(O)₂-alkyl, —N(R¹)-alkyl,—C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl, —N(R²¹)—C(O)—N(R²¹)-alkyl,—N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl, —N(R²¹)—S(O)₂—N(R²¹)-alkyl,—S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl, (7) heteroalkyl,—O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl, —S-heteroalkyl,—S(O)-heteroalkyl, —S(O)₂-heteroalkyl, —N(R¹)-heteroalkyl,—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl, (8) alkenyl,—O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl, (9) alkynyl, —O-alkynyl,—C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl, —S(O)-alkynyl, —S(O)₂-alkynyl,—N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl, —N(R²¹)—C(O)-alkynyl,—N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl, (10) aryl, —O-aryl,—C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl, —N(R¹)-aryl,—C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl, —N(R²¹)—C(O)—N(R²¹)-aryl,—N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl, —N(R²¹)—S(O)₂—N(R²¹)-aryl,—S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl, or (11) heteroaryl,—O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S-heteroaryl,—S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R²¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl, wherein saidheteroalkyl of (7), said heterocycloalkyl of (3), saidheterocycloalkenyl of (5), and said heteroaryl of (11) may be connectedthrough any available carbon or heteroatom, and wherein said alkyl, saidheteroalkyl, said cycloalkyl, said heterocycloalkyl, said aryl, saidheteroaryl, said alkenyl, said alkynyl, said cycloalkenyl, and saidheterocycloalkenyl of (1) through (11) are unsubstituted or substitutedwith one or more groups independently selected from R²; G is selectedfrom the group consisting of: (1a) hydrogen, halo, —NH₂, —OH, —SH,—SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO, (2a) cycloalkyl,—O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl, —S-cycloalkyl,—S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R¹)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl, (3a)heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R¹)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl, (4a)cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,—N(R¹)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl, (5a) heterocycloalkenyl,—O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R¹)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)-heterocycloalkenyl, (6a) alkyl, —O-alkyl, —C(O)-alkyl,—CO₂-alkyl, —S-alkyl, —S(O)-alkyl, —S(O)₂-alkyl, —N(R¹)-alkyl,—C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl, —N(R²¹)—C(O)—N(R²¹)-alkyl,—N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl —N(R²¹)—S(O)₂—N(R²¹)-alkyl,—S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl, (7a) heteroalkyl,—O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl, —S-heteroalkyl,—S(O)-heteroalkyl, —S(O)₂-heteroalkyl, —N(R¹)-heteroalkyl,—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl, (8a) alkenyl,—O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl, —N(R¹)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl, (9a) alkynyl,—O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl, —S(O)-alkynyl,—S(O)₂-alkynyl, —N(R¹)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl, (10a) aryl, —O-aryl,—C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl, —N(R¹)-aryl,—C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl, —N(R²¹)—C(O)—N(R²¹)-aryl,—N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl, —N(R²¹)—S(O)₂—N(R²¹)-aryl,—S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl, or (11a) heteroaryl,—O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S-heteroaryl,—S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R¹)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl; wherein saidheteroalkyl, said heterocycloalkyl, said heterocycloalkenyl, and saidheteroaryl of G may be connected through any available carbon orheteroatom, and wherein said alkyl, said heteroalkyl, said cycloalkyl,said heterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of G areunsubstituted or substituted with one or more groups independentlyselected from R²; each R¹ is independently selected from: (1b) hydrogenand —CHO, (2b) cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S(O)-cycloalkyl and —S(O)₂-cycloalkyl, (3b) heterocycloalkyl,—C(O)-heterocycloalkyl, —CO₂-heterocycloalkyl, —S(O)-heterocycloalkyland —S(O)₂-heterocycloalkyl, (4 b) cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S(O)-cycloalkenyl and —S(O)₂-cycloalkenyl, (5b)heterocycloalkenyl, —C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S(O)-heterocycloalkenyl and —S(O)₂-heterocycloalkenyl, (6b) alkyl,—C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl and —S(O)₂-alkyl, (7b) heteroalkyl,—C(O)-heteroalkyl, —CO₂-heteroalkyl, —S(O)-heteroalkyl and—S(O)₂-heteroalkyl, (8b) alkenyl, —C(O)-alkenyl, —CO₂-alkenyl,—S(O)-alkenyl and —S(O)₂-alkenyl, (9b) alkynyl, —C(O)-alkynyl,—CO₂-alkynyl, —S(O)-alkynyl and —S(O)₂-alkynyl, (10b) aryl, —C(O)-aryl,—CO₂-aryl, —S(O)-aryl and —S(O)₂-aryl, or (11b) heteroaryl,—C(O)-heteroaryl, —CO₂-heteroaryl, —S(O)-heteroaryl and—S(O)₂-heteroaryl, wherein said heteroalkyl, said heterocycloalkyl, saidheterocycloalkenyl, and said heteroaryl of R¹ may be connected throughany available carbon or heteroatom, and wherein said alkyl, saidheteroalkyl, said cycloalkyl, said heterocycloalkyl, said aryl, saidheteroaryl, said alkenyl, said alkynyl, said cycloalkenyl, and saidheterocycloalkenyl of R¹ are unsubstituted or substituted with one ormore groups independently selected from R²; each R²¹ is independentlyselected from H and C₁₋₆alkyl; each R² is independently selected from:(1c) halo, —NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO,(2c) cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl, (3c)heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl, (4c)cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,—N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl, (5c) heterocycloalkenyl,—O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R⁶)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkenyl, —S(O)—N(R²¹)-heterocycloalkenyland —S(O)₂—N(R²¹)— heterocycloalkenyl, (6c) alkyl, —O-alkyl,—C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl, —S(O)₂-alkyl,—N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,(7c) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl, (8c) alkenyl,—O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl, (9c) alkynyl,—O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl, —S(O)-alkynyl,—S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R²¹)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl, (10c) aryl, —O-aryl,—C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl, —N(R⁶)-aryl,—C(O)—N(R²¹)-aryl, —N(R²¹) C(O)-aryl, —N(R²¹)—C(O)—N(R²¹)-aryl,—N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl, —N(R²¹)—S(O)₂—N(R²¹)-aryl,—S(O)—N(R²¹)-aryl and —S(O)₂—N(R²¹)-aryl, (11c) heteroaryl,—O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S-heteroaryl,—S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl and —S(O)₂—N(R²¹)-heteroaryl, wherein saidheteroalkyl, said heterocycloalkyl, said heterocycloalkenyl, and saidheteroaryl of R² may be connected through any available carbon orheteroatom, and wherein said alkyl, said heteroalkyl, said cycloalkyl,said heterocycloalkyl, said aryl, said heteroaryl, said alkenyl, saidalkynyl, said cycloalkenyl, and said heterocycloalkenyl of R² areunsubstituted or substituted with one or more groups independentlyselected from R⁷; R³ is selected from H, methyl, ethyl, n-propyl andisopropyl; Z is a moiety selected from—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)OH, —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)OH,—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)—C(O)Oalkyl,—(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)—C(O)Oalkyl,

—(C(R¹¹)₂)—(C(R¹²R¹³))_(m)-Q, and —(C(R¹¹)₂)—(C(R¹⁴)₂)_(n)-Q, wherein Qis a moiety selected from the group consisting of:

wherein each R¹⁰ is independently H or alkyl; m is an integer from 0 to5; n is an integer from 0 to 5; p is an integer from 0 to 5; each R⁴ isindependently selected from H, —OH, C₁₋₃ alkyl, haloalkyl, alkoxy,heteroalkyl, cyano-substituted C₁₋₃ alkyl, hydroxy-substituted C₁₋₃alkyl, cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, heterocycloalkyl,—O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl; each R^(5A) isindependently selected from H, alkyl, haloalkyl, heteroalkyl,cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, or,alternatively, two R^(5A) groups are taken together with the carbon atomto which they are attached to form a carbonyl group, a spirocycloalkylgroup, a spiroheterocycloalkyl group, an oxime group, or a substitutedoxime group, said oxime substituents being independently selected fromalkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl; each R⁵ isindependently selected from H, —OH, alkyl, haloalkyl, alkoxy,heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl,cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl, and—O-alkyl-heterocycloalkyl, or, alternatively, two R⁵ groups bound to thesame carbon atom are taken together with the carbon atom to which theyare attached to form a carbonyl group, a spirocycloalkyl group, aspiroheterocycloalkyl group, an oxime group, or a substituted oximegroup, said oxime substituents being independently selected from alkyl,haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl; each R⁶ isindependently selected from: (1d) hydrogen, and —CHO, (2d) cycloalkyl,—C(O)-cycloalkyl, —CO₂-cycloalkyl, —S(O)-cycloalkyl, and—S(O)₂-cycloalkyl, (3d) heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S(O)-heterocycloalkyl, and—S(O)₂-heterocycloalkyl, (4d) cycloalkenyl, —C(O)-cycloalkenyl,—CO₂-cycloalkenyl, —S(O)-cycloalkenyl, and —S(O)₂-cycloalkenyl, (5d)heterocycloalkenyl, —C(O)-heterocycloalkenyl, —CO₂-heterocycloalkenyl,—S(O)-heterocycloalkenyl, and —S(O)₂-heterocycloalkenyl, (6d) alkyl,—C(O)-alkyl, —CO₂-alkyl, —S(O)-alkyl, and —S(O)₂-alkyl, (7d)heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl, —S(O)-heteroalkyl, and—S(O)₂-heteroalkyl, (8d) alkenyl, —C(O)-alkenyl, —CO₂-alkenyl,—S(O)-alkenyl, and —S(O)₂-alkenyl, (9d) alkynyl, —C(O)-alkynyl,—CO₂-alkynyl, —S(O)-alkynyl, and —S(O)₂-alkynyl, (10d) aryl, —C(O)-aryl,—CO₂-aryl, —S(O)-aryl, and —S(O)₂-aryl, (11d) heteroaryl,—C(O)-heteroaryl, —CO₂-heteroaryl, —S(O)-heteroaryl, and—S(O)₂-heteroaryl; each R⁷ is independently selected from: (1e) halo,—NH₂, —OH, —SH, —SO₂H, CO₂H, —SF₅, —OSF₅, cyano and —CHO, (2e)cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, —CO₂-cycloalkyl,—S-cycloalkyl, —S(O)-cycloalkyl, —S(O)₂-cycloalkyl, —N(R⁶)-cycloalkyl,—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—C(O)-cycloalkyl,—N(R²¹)—C(O)—N(R²¹)-cycloalkyl, —N(R²¹)—S(O)-cycloalkyl,—N(R²¹)—S(O)₂-cycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-cycloalkyl,—S(O)—N(R²¹)-cycloalkyl and —S(O)₂—N(R²¹)-cycloalkyl, (3e)heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl,—CO₂-heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl,—S(O)₂-heterocycloalkyl, —N(R⁶)-heterocycloalkyl,—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—C(O)-heterocycloalkyl,—N(R²¹)—C(O)—N(R²¹)-heterocycloalkyl, —N(R²¹)—S(O)-heterocycloalkyl,—N(R²¹)—S(O)₂-heterocycloalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heterocycloalkyl,—S(O)—N(R²¹)-heterocycloalkyl and —S(O)₂—N(R²¹)-heterocycloalkyl, (4e)cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, —CO₂-cycloalkenyl,—S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O)₂-cycloalkenyl,—N(R⁶)-cycloalkenyl, —C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—C(O)-cycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-cycloalkenyl,—N(R²¹)—S(O)-cycloalkenyl, —N(R²¹)—S(O)₂-cycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)-cycloalkenyl, —S(O)—N(R²¹)-cycloalkenyl and—S(O)₂—N(R²¹)-cycloalkenyl, (5e) heterocycloalkenyl,—O-heterocycloalkenyl, —C(O)-heterocycloalkenyl,—CO₂-heterocycloalkenyl, —S-heterocycloalkenyl,—S(O)-heterocycloalkenyl, —S(O)₂-heterocycloalkenyl,—N(R⁶)-heterocycloalkenyl, —C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—C(O)-heterocycloalkenyl, —N(R²¹)—C(O)—N(R²¹)-heterocycloalkenyl,—N(R²¹)—S(O)-heterocycloalkenyl, —N(R²¹)—S(O)₂-heterocycloalkenyl,—N(R²¹)—S(O)₂—N(R²¹)— heterocycloalkenyl,—S(O)—N(R²¹)-heterocycloalkenyl and —S(O)₂—N(R²¹)— heterocycloalkenyl,(6e) alkyl, —O-alkyl, —C(O)-alkyl, —CO₂-alkyl, —S-alkyl, —S(O)-alkyl,—S(O)₂-alkyl, —N(R⁶)-alkyl, —C(O)—N(R²¹)-alkyl, —N(R²¹)—C(O)-alkyl,—N(R²¹)—C(O)—N(R²¹)-alkyl, —N(R²¹)—S(O)-alkyl, —N(R²¹)—S(O)₂-alkyl,—N(R²¹)—S(O)₂—N(R²¹)-alkyl, —S(O)—N(R²¹)-alkyl and —S(O)₂—N(R²¹)-alkyl,(7e) heteroalkyl, —O-heteroalkyl, —C(O)-heteroalkyl, —CO₂-heteroalkyl,—S-heteroalkyl, —S(O)-heteroalkyl, —S(O)₂-heteroalkyl,—N(R⁶)-heteroalkyl, —C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—C(O)-heteroalkyl,—N(R²¹)—C(O)—N(R²¹)-heteroalkyl, —N(R²¹)—S(O)-heteroalkyl,—N(R²¹)—S(O)₂-heteroalkyl, —N(R²¹)—S(O)₂—N(R²¹)-heteroalkyl,—S(O)—N(R²¹)-heteroalkyl and —S(O)₂—N(R²¹)-heteroalkyl, (8e) alkenyl,—O-alkenyl, —C(O)-alkenyl, —CO₂-alkenyl, —S-alkenyl, —S(O)-alkenyl,—S(O)₂-alkenyl, —N(R⁶)-alkenyl, —C(O)—N(R²¹)-alkenyl,—N(R²¹)—C(O)-alkenyl, —N(R²¹)—C(O)—N(R²¹)-alkenyl, —N(R²¹)—S(O)-alkenyl,—N(R²¹)—S(O)₂-alkenyl, —N(R²¹)—S(O)₂—N(R²¹)-alkenyl,—S(O)—N(R²¹)-alkenyl and —S(O)₂—N(R²¹)-alkenyl, (9e) alkynyl,—O-alkynyl, —C(O)-alkynyl, —CO₂-alkynyl, —S-alkynyl, —S(O)-alkynyl,—S(O)₂-alkynyl, —N(R⁶)-alkynyl, —C(O)—N(R⁶)-alkynyl,—N(R²¹)—C(O)-alkynyl, —N(R²¹)—C(O)—N(R²¹)-alkynyl, —N(R²¹)—S(O)-alkynyl,—N(R²¹)—S(O)₂-alkynyl, —N(R²¹)—S(O)₂—N(R²¹)-alkynyl,—S(O)—N(R²¹)-alkynyl and —S(O)₂—N(R²¹)-alkynyl, (10e) aryl, —O-aryl,—C(O)-aryl, —CO₂-aryl, —S-aryl, —S(O)-aryl, —S(O)₂-aryl, —N(R⁶)-aryl,—C(O)—N(R²¹)-aryl, —N(R²¹)—C(O)-aryl, —N(R²¹)—C(O)—N(R²¹)-aryl,N(R²¹)—S(O)-aryl, —N(R²¹)—S(O)₂-aryl, —N(R²¹)—S(O)₂—N(R²¹)-aryl,—S(O)—N(R²¹)-aryl, and —S(O)₂—N(R²¹)-aryl, or (11e) heteroaryl,—O-heteroaryl, —C(O)-heteroaryl, —CO₂-heteroaryl, —S-heteroaryl,—S(O)-heteroaryl, —S(O)₂-heteroaryl, —N(R⁶)-heteroaryl,—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—C(O)-heteroaryl,—N(R²¹)—C(O)—N(R²¹)-heteroaryl, —N(R²¹)—S(O)-heteroaryl,—N(R²¹)—S(O)₂-heteroaryl, —N(R²¹)—S(O)₂—N(R²¹)-heteroaryl,—S(O)—N(R²¹)-heteroaryl, and —S(O)₂—N(R²¹)-heteroaryl, wherein saidheteroalkyl, said heterocycloalkyl, said heterocycloalkenyl, and saidheteroaryl of R⁷ may be connected through any available carbon orheteroatom; each R¹¹ is independently selected from H and C₁₋₃ alkyl;each R¹² is independently selected from H, C₁₋₃ alkyl, —OH, andhydroxy-substituted C₁₋₃ alkyl; each R¹³ is independently selected fromH, unsubstituted C₁₋₃ alkyl, and C₁₋₃ alkyl substituted with one or moregroups each independently selected from hydroxyl and alkoxy, or R¹² andR¹³ are taken together to form an oxo; and each R¹⁴ is independentlyselected from H and fluoro.
 2. A compound in accordance with claim 1wherein each V is independently selected from the group consisting of:C₁₋₆alkyl and cycloalkyl.
 3. A compound in accordance with claim 1wherein: G is selected from the group consisting of: (1a) hydrogen,halo, —NH₂, —OH, CO₂H, and cyano; (2a) cycloalkyl, —O-cycloalkyl, and—N(R¹)-cycloalkyl; (3a) heterocycloalkyl, —O-heterocycloalkyl, and—N(R¹)-heterocycloalkyl; (6a) alkyl, —O-alkyl and —N(R¹)alkyl; (7a)heteroalkyl, —O-heteroalkyl, and —N(R¹)-heteroalkyl; (8a) alkenyl,—O-alkenyl, and —N(R¹)-alkenyl, (9a) alkynyl, —O-alkynyl, and—N(R¹)-alkynyl; (10a) aryl, —O-aryl, —C(O)-aryl, —S-aryl, —S(O)-aryl,—S(O)₂-aryl, —N(R¹)-aryl, —C(O)—N(R²¹)-aryl; (11a) heteroaryl,—O-heteroaryl, —C(O)-heteroaryl, —S-heteroaryl, —S(O)-heteroaryl,—S(O)₂-heteroaryl, —N(R¹)-heteroaryl, —C(O)—N(R²¹)-heteroaryl; whereinsaid heteroalkyl, heterocycloalkyl, heterocycloalkenyl, and heteroarylof G are connected through any available carbon or heteroatom, andwherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,said heteroaryl, alkenyl, alkynyl, cycloalkenyl, and heterocycloalkenylof G are unsubstituted or substituted with one or more groupsindependently selected from R².
 4. A compound in accordance with claim 1wherein G represents a phenyl group optionally substituted with 1-3groups selected from halo, C₁₋₃alkyl, C₁₋₃ alkoxy, haloC₁₋₃alkyl andhaloC₁₋₃alkoxy, or with one phenyl ring that is optionally substitutedwith 1-3 halo atoms.
 5. A compound in accordance with claim 1 wherein L¹is selected from the group consisting of—N(R⁴)—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—N(R⁴)—,—O—(C(R^(5A))₂)—(C(R⁵)₂)_(q)—,—(C(R^(5A))₂)—(C(R⁵)₂)_(r)—(C(R^(5A))₂)—O—, and—(C(R^(5A))₂)—(C(R⁵)₂)_(s)—.
 6. A compound in accordance with claim 1wherein L¹ is selected from the group consisting of a bond, —NH—(CH₂)₂—,—O—(CH₂)₂—, —O—, —NH—, —N(CH₃)—, —CH₂—, —CH(C₁₋₆alkyl)- and—CH(C₃₋₆cycloalkyl)-.
 7. A compound in accordance with claim 1 whereinL¹ is selected from the group consisting of —CH₂—, —CH(CH₃)—, —CH₂CH₂—,—CH(CH₂CH₂CH₂CH₃)—, —CH(CH(CH₃)₂)—, —CH(cyclopropyl)- and—CH(CH₂CH₂(CH₃)₂—.
 8. A compound in accordance with claim 1 wherein ringB is phenyl.
 9. A compound in accordance with claim 1 wherein ring B isa 5-6 membered heteroaromatic ring selected from the group consistingof: thiophene, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.10. A compound in accordance with claim 1 wherein R³ is H or is selectedfrom the group consisting of: methyl, ethyl, n-propyl, and isopropyl.11. A compound in accordance with claim 1 wherein Z is —CH₂CH₂C(O)OH.12. A compound in accordance with claim 1 wherein Z is


13. A compound represented by Formula (A):

or a pharmaceutically acceptable salt thereof, wherein: each V isindependently selected from the group consisting of: C₁₋₆alkyl andcycloalkyl; G represents a phenyl group optionally substituted with 1-3groups selected from halo, C₁₋₃alkyl, C₁₋₃alkoxy, haloC₁₋₃alkyl andhaloC₁₋₃alkoxy, or with one phenyl ring optionally substituted with 1-3halo atoms; L¹ represents —(C(R^(5A))₂)—(C(R⁵)₂)_(s)—; wherein s is 0-1,each R^(5A) represents H, C₁₋₆alkyl or C₃₋₆cycloalkyl, and when present,each R⁵ represents H; ring B is phenyl. R³ is H; Z is selected from thegroup consisting of: —CH₂CH₂CO₂H, and

wherein p is 0-2 and when present each R¹¹ is H.
 14. A compound inaccordance with claim 1 selected from Table 1: TABLE 1

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound in accordance with claim 1 or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.
 16. A method of treating type 2diabetes mellitus in a mammalian patient in need of such treatmentcomprising administering to the patient a compound in accordance withclaim 1 in an amount that is effective to treat type 2 diabetesmellitus.